IL194591A

IL194591A - 6-CYCLICAMINO-7-OXO-8-ALKYL-PYRIDINE[3,4-b]PYRAZINE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME AND THEIR USE IN THE PREPARATION OF MEDICAMENTS

Info

Publication number: IL194591A
Application number: IL194591A
Authority: IL
Original assignee: Pfizer Prod Inc
Priority date: 2006-04-21
Filing date: 2008-10-07
Publication date: 2012-07-31
Also published as: US20070249615A1; TWI337609B; DK2013208T3; EP2013208A1; EP2013208B1; PE20080192A1; UY30291A1; ES2366239T3; CU20080194A7; CN101454320A; AP2408A; CN101454320B; CY1111739T1; TNSN08408A1; EA014919B1; GT200700035A; MEP23808A; ZA200808283B; NL2000583A1; TW200808794A

Description

194591/2 ΠΠΊ Ν D^DTDil T^Kl -H D^UDIl ,ϋ ΙΓΤΝΤΕ) [B-4,3] ΓΡΤΈΙ D"Nign DITHDJI ηηπιι ο ιιπττϋη PYRIDINE [3,4-B] PYRAZINONES, PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME AND USES THEREOF IN THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS 194591/2 FIELD OF THE INVENTION The present Invention comprises a class of pyridine [3,4-b] pyrazinone compounds having the structure of Formula I and pharmaceutical compositions comprising a compound of Formula I. The present Invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of Formula I to the subject, in general, these compounds inhibit, in whole or in part, the enzyme: cyclic guanylate monophosphate-speclfic phosphodiesterase type 5 BACKGROUND OF THE INVENTION The prevalence of hypertension in developed countries is about 20% of the adult population, rising to about 60-70% of those aged 60 or more. Hypertension Is associated with an increased risk of stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal Impairment. Despite the large number of antl-hypertenslve drugs available In various pharmacological categories, additional agents useful for the treatment of hypertension are still needed.

Vascular endothelial cells secrete nitric oxide (NO). This acts on vascular smooth muscle cells and leads to the activation of guBnylate cyclase and the accumulation of cyclic guanosine monophosphate (cGMP). The accumulation of cGMP causes the muscles to relax and the blood vessels to dilate, leading to a reduction in blood pressure. The cGMP is inactivated by hydrolysis to guanosine ^-monophosphate (GMP) by a cGMP-specific phosphodiesterase. One important cGMP-phosphodiesterase has been identified as phosphodiesterase type 5 (PDE5). Inhibitors of PDE5 decrease the rate of hydrolysis of cGMP and so potentiate the actions of nitric oxide.

Improved drug therapies for the treatment of subjects suffering from or susceptible to a cardiovascular condition are desirable. In particular, there still is a need for a new class of PDE-5 inhibitors for treating cGMP-medlated conditions and corresponding drug therapies.

SUMMARY OF THE INVENTION In one embodiment, the invention comprises compounds having the structure of Formula I: wherein R2, R6A, R8B, and R8 are as defined in the detailed description of the invention.

In another embodiment, the invention comprises a pharmaceutical composition comprising a compound having the structure of Formula I, In another embodiment, the invention comprises methods of treating a condition in a subject by administering a therapeulicaily effective amount of a compound having the Formula I to the subject. The conditions that can be treated in accordance with the present invention include cardiovascular conditions, metabolic conditions, centra! nervous system conditions, pulmonary conditions, sexual dysfunction, and renal dysfunction.

In another embodiment, the invention comprises a method for inhibiting PDE-5, and particularly methods for treating a condition (typically a pathological condition) mediated by PDE-5 by administering a compound having a structure of Formula I to the subject.

In another embodiment, the invenlion comprises methods of making compounds having the structure of Formula I.

In anolher embodiment, the Invention comprises Intermediates useful in the synthesis of compounds having the structure of Formula I.

DETAILED DESCRIPTION OF THE INVENTION This detailed description of embodiments is intended only to acquaint others skilled in the art with Applicants' inventions, its principles, and its practical application so that others skilled in the art may adapt and apply the inventions in their numerous forms, as they may be best suited to (he requirements of a particular use. These inventions, therefore, are not limited to the embodiments described in this specification, and may be variously modified.

A. Abbreviations and Definitions As used in reference to Ή NMR, the symbol "5"refers to a 1H NMR chemical shift.

As used in reference to 1H NMR, the abbreviation "br" refers to a broad 1H NMR signal.

As used in reference to 1H NMR, the abbreviation "d" refers to a doublet H NMR peak.

As used in reference to Ή NMR, the abbreviation "dd" refers to a doublet of doublets 1H NMR peak.

The abbreviation "HRMS" refers to High Resolution Mass Spectrocopy (eleclrospray ionisation positive scan).

The abbreviation "m/z" refers to a Mass spectrum peak.

As used in reference to Ή NMR, the abbreviation "m" refers to a multiplet 1H NMR peak.

As used in reference to 1H NMR, the abbreviation "q" refers to a quartet 1H NMR peak.

As used in reference to 'H NMR, the abbreviation "s" refers to a singlet Ή NMR peak.

As used in reference to 1H NMR, the abbreviation "t" refers to a triplet H NMR peak.

The abbreviation "TFA" refers to trifluoroacetic acid.

The term "alkyl" (alone or in combination with other term(s)) refers to a linear or branched-chain saturated hydrocarbyl substituted (i.e., a substitutent containing only carbon and hydrogen) typicaily containing from about one to about twenty carbon atoms or; in another embodiment from about one to about twelve carbon atoms; in another embodiment, from about one to about ten carbon atoms; in another embodiment, from about one to about six carbon atoms; and In another embodiment, from about one to about four carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like.

The term "alkenyl" (aione or In combination with other term(s)) refers to a linear or branched- chain hydrocarbyi substituent containing one or more double bonds and from about two to about twenty carbon atoms; in another embodiment, from about two to about twelve carbon atoms;in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 3-methylbutenyl.

The terms "alkenyl", and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "Z" and "E" orientations.

The term "aikynyl" (alone or in combination with other term(s)) refers to linear or branched-chain heterocarbyl substiluents containing one or more triple bonds and from about two to about twenty carbon atoms; In another embodiment, from about two to about twelve carbon atoms; in another embodiment, from about two to about six carbon atoms; and in another embodiment, from about two to about four carbon atoms. Examples of aikynyl radicals include 1-propynyl, 2-propynyl, 1 -butyne, 2-butynyl and 1-pentynyl.

The term "amino", alone or in combination with another term(s), refers to -NH2 when it is at a terminal position or to -NH— when it is used in combination with another term(s) and is not at a terminal position.

The term "ary , alone or in combination with another term{s), refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together In a pendent manner or may be fused. Examples of aryl moieties include phenyl, naphlhyl, tetrahydronaphthyl, indanyl and biphenyl.

The term "carboxy", alone or in combination with another term(s , refers to a radical of the formula -C(0)OH.

The term "cyano", alone or in combination with another term(s), means -CN, which also may be depicted; The term "cycloalkyl", alone or in combination with another term{s), refers to saturated carbocyclic radicals having three to about twelve carbon atoms. In another embodiment, cycloalkyl radicals are "tower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexy!.

The term "cycloalkylalkyl", alone or in combination with another term(s), refers to alkyl substituted with cycloalkyl. Examples of such subslltuents include cyclopropy!methyl, cyclobutylmethyl, cyclopentylme!hyl, and cyclohexylmethyl.

The term "cycloalkenyl", alone or in combination with another term(s), refers to a partially unsaturated carbocyclyl substituent. Examples of such substituenls include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

The term "halogen" or "halo", alone or in combination with another term(s), refers to means a fluorine radical (which may be depicted as -F), chlorine radical (which may be depicted as -CI), bromine radical (which may be depleted as -Br), or iodine radical (which may be depicted as -I). In another embodiment, the halogen is a fluorine or chlorine radical. In another embodiment, the halogen is a fluorine radical.

When used in combination with another term(s), the prefix "halo" Indicates that the substituent to which the prefix is attached Is substituted with one or more Independently selected halogen radicals, For example, haioa!kyl refers to an alkyl substituent wherein at least one hydrogen radical is replaced with a halogen radical. Where there are more than one hydrogens replaced with halogens, the halogens may be the same or different. Examples of haloalkyls include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, dif!uoromethyl, trifluoromethyl, 2,2,2-trlfluoroelhyl, dif!uoroethyl, pentaffuoroethyl, difJuoropropyl, dichloropropy!, and heptafluoropropyl. illustrating further, "haloalkoxy" means an a!koxy substituent wherein at least one hydrogen radical is replaced by a halogen radical, Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"); and 2,2,2,-frlfluoroethoxy. If a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).

A heterocyclyl may be a single ring, which typically contains from 3 to 10 ring atoms, more typically from 3 to 7 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, dihydrofurnayl, tetrahydrofurnayl, thiophenyl (also known as "thlofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidlnyl, imidazoly!, isoimidazoiyl, imldazolinyl, imidazolidinyl, pyrazoiyl, pyrazollnyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathlolyl, oxazolyi, isoxazolyl, thiazolyl, isothlazoiyl, thiazolinyl, isothiazolinyl, thlazo!ldinyl, isothiazolidinyl, thlodiazolyl, oxathiazoly), oxadiazolyl (including oxadiazolyl, 1 ,2,4-oxadiazolyl (also known as "azoxlmyl"), 1 ,2,5-oxadiazo!yi (also known as "furazanyl"), or 1 ,3,4-oxadiazolyl), oxatrlazolyl (including 1 ,2,3,4-oxatriazolyl or 1 ,2,3, 5-oxatriazo!yl), dioxazolyl (including 1 ,2,3-dioxazolyl, 1 ,2,4-dloxazolyl, 1 ,3,2-dioxazolyl, or 1 ,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathlolanyl, pyranyl (including 1 ,2-pyranyl or 1 ,4-pyranyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1 ,3-diazinyl" or "pyrlmidyl"), or pyrazinyl (also known as "1,4-diazinyl")), piperazinyJ, Iriazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known 1.2.4- triazinyl), and v-triazinyl (also known as "1 ,2,3-triazinyl")), oxazinyl (including 1 ,2,3-oxazinyl, 1 ,3,2-oxazinyl, 1 ,3,6-oxazinyl (also known as "pentoxazolyl"), 1 ,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-tsoxazinyl or p-isoxazinyl), oxazoiidinyl, Isoxazolidinyl, oxathiazlnyl (Including 1.2.5- oxathiazinyl or 1 ,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazlnyl or 1 ,3,5,2-oxadiazinyl), morphoiinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl, A heterocyclyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom {e.g., nitrogen, oxygen, or sulfur). Examples of 2-fused-ring heterocyclyls include, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-qulnolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyridot4,3-b]-pyridinyl), and pteridinyl, indolyl, Isoindolyl, Indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyi, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzlmidazoiyl, benzotriazolyl, benzoxazinyl, benzisoxaziny!, and tetrahydrolsoquinolinyl, Other examples of fused-rlng heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinollhyl (also known as -benzazinyl") or isoquino!inyl (also known as "2-benzazInyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (Including cinnolinyl (also known as "1,2-benzodiazinyJ") or quinazolinyl (also known as "1,3-benzodiazinyr)), benzopyranyl (including "chromanyl" or "isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as "benzlsoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyi (also known as "coumaronyl"), Isobenzofuranyl, benzothienyl (also known as "benzothiopheny!," "thionaphtbenyl," or "benzothiofuranyl"), Isobenzothlenyl (also known as "isobenzothiopheny!," "isothionaphthenyl," or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxaztnyl , 1,4,2-benzoxazlnyl , 2,3,1-benzoxazlnyl , or 3,1 ,4-benzoxazinyl ), benzisoxazlnyl (including 1,2-benzlsoxazinyl or 1 ,4-benzlsoxazinyl), tetrahydrolsoquinolinyl , carbazolyl, xanthenyl, and acridinyt.

The term "heteroaryl", alone or in combination with another term(s), refers to a completely unsaturated (i.e., aromatic) heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may comprise a single ring or 2 or 3 fused rings. In one embodiment, heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two beteroatoms selected from sulphur, nitrogen and oxygen, selected from thlenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyt, pyridyl and pyrazinyl. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimldinyl, and pyridazinyl; 5-membered ring subs!ituents such as 1,3,5-, 1,2,4- or 1.2.3- trtazinyl, imidazyl, furanyi, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, and thiazotyl; 1 ,2,3-, 1.2.4- , 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothlazolyl; 6/5-membered fused ring substltuents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1 ,2-, 1 ,4-, 2,3- and 2, 1-benzopyronyl, quinoiinyl, isoquinolinyl, cinnolinyi, qulnazo/inyl, and ,4-benzoxazinyl. Other heteroaryts include unsaturated 5 to 6 membered heteromonocyc!yl groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imtdazolyl, pyrazoiyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimldyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H- 1 ,2,4-triazotyl, 1 H-1 ,2.3-tnazolyl, 2H-1 ,2,3-triazolyl]; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indoly!, isoindoiyi, tndolizinyl, benzimidazoly!, quinolyl, isoquinolyl, indazolyl, benzoiriazolyl, tetrazolopyrfdazinyl [e.g., tetrazoio [1 ,5-bJpyrldaztnyl]; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyi, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, isoxazolyl, oxadiazolyi (e.g., 1,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,2,5-oxadfazolyfJ; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadlazolyl]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1 ,2,4- thiad!azolyl, 1,3,4- thiadiazolyi, 1 ,2,5-thiadiazolyi]; unsaturated condensed heterocyclic groups containing 1 to 2 suffur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

The term "heterocyclylalkyl", alone or in combination with another term(s), refers to alkyl substituted with a heterocyclyl.

The term "hydroxy", alone or in combination with another term(s), refers to -OH.

The term "mercapto" or "thiol" refers to a sulfhydryl subslituent, which also may depicted as -SH.

The term "nitro", alone or in combination with another term(s), refers to -NO2.

The term "sulfonyf", alone or In combination with another term(s), refers to -S(0)2-, which also may be depicted as: Thus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S(0)2-alkyl. Examples of typically preferred afkylsulfonyl substltuents include methy!sulfonyl, ethylsulfonyl, and propylsulfonyl.

The term "sulfoxyl" , alone or in combination with another term(s), refers to -S(O) -, which also may be depicted as: 0 II The term "thfo" or "thia", alone or in combination with another term(s), refers to a thiaether substituent, an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as -S-. This, for example, "alkyj-thio-atkyl" means alkyl-S-alkyl.

If a substituent is described as being "optionally substituted", the substituent may be either (1 ) not substituted, or (2) substituted. If a carbon of a substituent Is described as being optionally substituted with one or more of a list of subslituenis, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. This specification uses the terms "substituent" and "radical" interchangeably.

The term "PDE5-mediated condition" refers to any condition mediated by PDE5.

The term "composition" refers to an article of manufacture which results from the mixing or combining of more than one element or ingredient.

The term "hypertensive subject" refers to a subject having hypertension, suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.

The term "pharmaceutically acceptable carrier" refers to a carrier that is compatible with the other ingredients of the composition and is not deleterious to the subject. Such carriers may be pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent. The preferred composition depends on the method of administration.

The terms "prevent," "prevention" or "preventing" refer to either preventing the onset of a preclinically evident condition altogether or preventing the onset of a preclinical evident stage of a " condition in a subject. Prevention includes, but is not limited to, prophylactic treatment of a subject at risk of developing a condition.

The term "therapeutically effective amount" refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.

The term "treatment" (and corresponding terms "treat" and "treating") includes palliative, restorative, and preventative treatment of a subject. The term "palliative treatment" refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition. The term "preventative treatment" (and the corresponding term "prophylactic treatment") refers to treatment that prevents the occurrence of a condition In a subject. The term "restorative treatment" refers to treatment that halls the progression of, reduces the pathologic manifestations of,' or entirely eliminates a condition in a subject.

B. Compounds The present invention comprises, in part, a novel class of pyridine [3,4-b] pyrazinone compounds. These compounds are useful as inhibitors of PDE5.

Compounds of Formula (I) As used herein, compounds of the present invention include tautomers of the compounds and pharmaceutically acceptable salts of the compounds and tautomers.

The present invention is directed, in part, to a class of compounds having the structure of Formula I: wherein R2 Is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein said R2 aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyi, -OR201, -C(O)R:0\ -OC(0)R201, -C(0)OR201, -NR2o R20∑, - N(R20i)C(O}R202, -CfOJNR^R202, -C(O)NR201C(O)R202, -SR201, -S(0)R20', and -S(0)zR201; wherein said alkyl, alkenyl, and alkynyl and cycloalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and - 203, C(0)OR R201, R and R are independently selected from the group consisting of hydrogen and alkyl, wherein said aikyl may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, hydroxy, alkoxy, carboxy and -C(0}NH2; ReA and R6B together with the nitrogen to which they are attached form a partially or fully saturated 3 to 14 membered ring heterocyclyl, wherein the heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, ,601 ,601 o 602 halogen, oxo, alkyl, alkenyl, alkynyl, cyano, -OR6"', -C(0)R6 , -OC(0)Rou\ - C(0)OReo\ -NR°U1R -N(Re0 )C(O)R8C2, -C(O)NRe0,RM2, -C(O)NR601C(O)Re02t cycloalkyi, aryl, and heterocyclyl, wherein {a) said alkyl, alkenyl, alkynyl and cycloalkyi substituents may be optionally substituted with one or s more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR , C(0)Re°3, -C(O)ORe03, -OC(O)R603r -NReMR6(M, -N{R603)C(O)R61M, -C(0)NR tV°\ - C(O)NRe03C(O)R60\ -SR603, -S(0)R603, -S(0)2R603, · N(R603)S(O)2RBW, and -S(O)2NR603R60', C(O)NR6D3C(O)Re04, -SRe03, -S(O)RfiD3, -S(O)2RB03, -N{R603)S(O)2R604, and -S(O):NR603Re04, and (b) said ary! and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cyano, oxo, - OR601, -C(0)R601, -C(O)ORe0\ -OC(O)R60\ -NR601R602, -N(R60,)C(O)R602, -C(O)NRe01R60!, - C(O)NRS0,C{O)Re02, -SR601, -S(0)R602, -S(0)2R601, -N(Re01)S(O)2R602, and -S(O)=NR601Re02; R601, R , R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) said R601 and Rs°2 alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloa!kynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) said Re01 and R alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy; Re is alkyl; wherein said R8 substltuent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, alkenyl, alkynyl, -OR601, -C(O)Re0\ -C(0)OReo\ -OC(0)Reo\ -NReQ Reci, -N(Ra01)C(O)R802, - C(O)NRe01Re02, and -C(O)NRe01C(O}RiK, wherein said alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, and alkoxy; and R801 and Re02 are Independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl, wherein (a) when said alkyl Is methyl, said methyl may be optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when said alkyl comprises at least two carbon atoms, said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (c) said Rfl01 and R802 alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

Selected subclasses of compounds of interest that fall within the scope of the compounds of Formula 1 are shown in Table A, wherein R2, ReA, RBB and Re are as defined for compounds of R9, R 10( Rn R 13 are g e|ec tec) from tne group consisting of hydrogen, halogen, Ci to C. afkyl, -OR!01 , and -NRM1Rzo:;; wherein (a) when the alkyJ is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, C, to C2 alkoxy and hydroxy; and wherein R201 and R202 are independently selected from the group consisting of hydrogen and Ct to C2 alkyl; and ■RR R,S, R S, R 7, R'eand R^ are selected from the group consisting of hydrogen, halogen, alkyl, and -OR601 , wherein (a) said alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OReM, -C(0)R603, - C(0)OR603 ,-NR6MR6W, and -C(O)NR603RI04; and R601, REM and Rm are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, R9, R10, R 1, R12, R13 are selected from the group consisting of hydrogen, halogen, C, to £, alkyl, -OR201, and -NR201R202; wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, Ci to C2 alkoxy and hydroxy; and wherein R20' and R102 are independently selected from the group consisting of hydrogen and C, to C2 alkyl.

In another embodiment, RFL- R 0, R11, R'2, R 3 are selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trlfluoromethyi, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, and- diethylamino, In another embodiment, R'4, R15, R1FL, R17, R,e and R19 are selected from the group consisting of hydrogen, alkyl, and -OR801, wherein (a) said alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of -OR803, -C(0)R603, - C(0)OR6M,- and -C{0)NR6WReo4,' and Re0\ R603 and RM* ere independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, R'4, R1B, R18, R17, R e and R19 are selected from the group consisting of hydrogen, OH, -CH3, -CH2CH3, -CH:CHiCH3, -C(CH3)2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -CH2CH:CH2OH -CH2CH(CH3}OH, -CH(CH3)CH(CH3)OH, -CH2C(CH3)2OH, -CH2C(0)OH, - CH2C(0)OC(CH3)3, and -C(0)NH2.

Embodiments of R1 Substituent In one embodiment of Formula I, R2 is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein R2 may be optionally substituted as provided in Formula I.

In one embodiment of Formula I, R2 Is selected from the group consisting of phenyl and a 3 to 10 membered ring heleroaryl, optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl and a 5 to 7 membered ring heterocyciyi, optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl and a 5 to 7 membered ring heleroaryl, optionally substituted as provided in Formula I, In another embodiment of Formula f, R2 is selected from the group consisting of phenyl and a 5 to 6 membered ring heteroaryl, optionally substituted as provided in Formula I. In another embodiment of Formula I, Rz is a 5 to 6 membered ring heteroaryl that comprises 1 , 2, or 3 ring heteroa'toms selected from the group consisting of oxygen and nitrogen.

In one embodiment of Formula !, RJ is selected from the group consisting of phenyl, thienyi, furany), Ihlazolyl, imidazolyl, pyrazolyl, isoxazoiyl, isothiazolyl, pyrazlnyl pyridinyl, triazlnyl, imidazyl, thiophenyl, pyrazoiyi, oxazolyl, oxadiazolyl, pyridyl, pyrazyl, pyrimldinyl, pyridazlnyl, benzofuran, and benzodioxolyl. in another embodiment of Formula I, Rc Is selected from the group consisting of phenyl, pyridinyl, pyrimidlnyl, isoxazoiyl, pyrazoiyi, benzofuran, and benzodioxolyl, optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl, and pyridinyl optionally substituted as provided In Formula I.

In another embodiment of Formula I, R! is selected from the group consisting of phenyl, each optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 Is selected from the group consisting of phenyl, each optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, each optionally substituted as provided In Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, , each optionally substituted as provided in Formula I. In another embodiment of Formula I, Rz is selected from the group consisting of phenyl and pyridinyl, each optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is phenyl optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is pyridinyl optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of phenyl and , each optionally substituted as provided in Formula I. In another embodiment of Formula I, R2 is selected from the group consisting of , each optionally substituted as provided in Formula I. In another embodiment, R" is , optionally substituted as provided in Formula 1-1.

In one embodiment of Formula I, R2 may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, -OR201, - C(0)OR201, -NR20 R 02 and -C(O)NR201R202, wherein the alkyl substituted may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(0)OR M; wherein Rr° R2M, and ROT3 are independently selected from the group consisting of hydrogen and C, to C alkyl.

In another embodiment of Formula I, R2 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, to C4 alkyl, -OR201, -NR201RECZ, -C{0)OR201, and -C(0)NRB1RiK, wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, C, to C alkoxy and hydroxy; and wherein R201 and R202 are independently selected from the group consisting of hydrogen and d to C2 alkyl.

In another embodiment of Formula I, R2 may be optionally substituted with one or more substituents selected from the group consisting of halogen, C, to C, alkyl, -OR201, and -NR201R202; wherein (a) when the alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 halogen substituents, (b) when the alkyl comprises at least two carbon atoms, the alkyl may be optionally substi!uied with one or more substiluenis selected from the group consisting of halogen, oxo, C, to C2 alkoxy and hydroxy; and wherein R201 and RZM are independently selected from the group consisting of hydrogen and C, to C2 alkyl.

In one embodiment of Formula I. R2 may be optionally substituted with one or more substituents selected from the group consisting of chloro, fiuoro, methyl, ethyl, propyl, butyl, pentyl, hexyl, trifluoromethyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, elhylamlno, and diethylamino. In another embodiment of Formula f, R2 may be optfonafly substituted with one'or more substituents selected from the group consisting of fiuoro, methyl, trifluoromethyl, methoxy, trifluoromelhoxy, amino, methylamino, and dimethylamino. tn one embodiment of Formula I, R* is substituted with one or more fiuoro substituents. In another embodiment of Formula I, R2 is substituted with one fiuoro substituent. In another embodiment of Formula ), R2 is substituted with two fiuoro substituents.

In one embodiment of Formula I, R2 is substituted with methoxy.

In one embodiment of Formula I, R2 is substituted at the para position with a substituent selected from the group consisting of fiuoro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, methylamino, and dimethylamino. in another embodiment of Formula I, R2 is substituted at the para position with a substituent selected from the group consisting of fiuoro, methyl, trifluoromethyl, methoxy, and trifluoromethoxy. In another embodiment of Formula I, R2 is substituted at the para position with methoxy.

In one embodiment of Formula 1, R: Is sefected from the group in Table A consisting of Formula 1-1 , Formula I-5, Formula I-6, and Formula 1-1 1 , , wherein Rfl, R10, R11. R12 and R13 are independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, -OR201, -C(O)R20\ -OC(0)R201, -C(0)OR201, -NR2Q,R20Z and -C{0)NRZ01R202, wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(O)ORJ0S; wherein R20 , R202, and R203 are Independently selected from the group consisting of hydrogen and tod alkyl. In another embodiment of Formula I, R2 is selected from the group in Table A consisting of Formula 1-1 and Formula I-6, wherein R8, R10, R11, R12 and R 3 are independently selecled from (he group consisting of hydrogen, halogen, oxo, alkyl, -OR20', -C(O)RZ01, -OC(0)RM1, -C(O)ORZ0\ -NR201R202 and -C(0)NR2 1R2CZ„ wherein the alkyl substitutent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(O)ORz03; wherein R201 , R:°2, and R203 are independently selected from the group consisting of hydrogen and C, to C. alkyl. In another embodiment of Formula I, Rz is selected from the group in Table A consisting of Formula 1-1, and Formula !-5, wherein R9, R,0( R^ R^ a d 13 are independently selected from the group consisting of hydrogen, halogen, a!kyi, haloalkyi, oxy, alkoxy, hydroxy, and carboxy. In another embodiment of Formula I, R2 is selected from the group in Table A consisting of Formula 1-1 , and Formula I-6, wherein RB, R 0, R11, R12 and R13 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy. In another embodiment of Formula I, Rz is selected from the group in Table A consisting of Formula 1-1 and Formula I-6, wherein Re, R10, R,1, R1z and R 3 are independently selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy.

In another embodiment of Formula I, P? is as provided in Formula I-3 in Table A, wherein R11 is selected from the group consisting of hydrogen, fluoro, methyl, trifluoromethyl, and methoxy. In another embodiment of Formula I, the R2 substituent is as provided in Formula I-4 in Table A, Embodiments of -NRi ReB Substituent In one embodiment of Formula I, R6A and R6B together with the nitrogen to which they are attached form a partially or fully saturated 3 to 14 membered ring heterocyclyl, optionally substituted as provided in Formula I. In another embodiment, R6Aand RBB together with the nitrogen to which they are attached form a partially or fully saturated 5 to 7 membered ring heterocyclyl, optionally substituted as provided in Formula I. In another embodiment, ReA and RSB together with the nitrogen to which they are attached form a partially or fully saturated 5 to 6 membered ring heterocyclyl, optionally substituted as provided in Formula I, In one embodiment of Formula I, R6Aand ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyt, piperazinyi, morpholinyl, and dlazapinyl, wherein the pyrrolidinyl, piperadinyl, p!perazinyl, morpholinyl, and diazapinyl may be optionally substituted as provided in Formula I.

In another embodiment, Rw and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of each optionally substituted as provided in Formula I.

In-another embodiment, R and R together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of , and , each optionally substituted as provided in Formula I. In another embodiment, R and ReB together with the nitrogen to which they are attached form a plperazinyl as provided in Formula 1-22, In one embodiment, the RBAand RBB heterocyclyl may be optionally substituted with one or more substltuenls independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -OR801, -C(0)R601, - C(O)ORe01, -NRe01Re02, -N(R6D,)C{O)Re02, -C(0)NR6D1Reo\ wherein (a) said alkyl substituent may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR603, -C(0)RSM, -C(O)ORfl03,-NRe03Re04, and - C(O)NR603R60"; and R601, R602, Re03 and R60" are independently selected from the group consisting of hydrogen and alkyl, wherein (a) said Re01 and RM2 alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

In another embodiment, the R6A and ReB heterocyclyl may be optionally substituted with one or more substiiuents independently selected from the group consisting of hydrogen, halogen, alkyl, and -ORe01, wherein (a) said alkyl substituent may be optionally substituted with one or more substituents independently selected from Ihe group consisting of halogen, -OR603, -C(0)R603, -C(0)OR6D3,-NRfl03R6W, and -C(O)NR603R604; and R601, Rm and Rm are Independently selected from the group consisting of hydrogen and a!kyl.

In anoiher embodiment, the ReA and Res heterocyclyl may be optionally substituted with one or more substituents Independently selected from the group consisting of hydrogen, halogen, alkyl, and -OR601, wherein (a) said alkyl subslituent may be optionally substituled with one or more substituents independently selected from the group consisting of halogen, -OR603, -C{O)Re03, -C(0)OReo3,-NR«nR«w an d .Cio)N R603R604; gnd Reoi_ R603 and R.o4 a(¾ jnciependentiy selected from the group consisting of hydrogen and alkyl.

In another embodiment, the R and R heterocyclyl may be optionally substituted with one or more substituentsjndependently selected from the group consisting of hydrogen, alkyl, and -OR601, wherein {a) said alkyl substiluent may be optionally substituted with one or more substituents independently selected from the group consisting of -OR603, -C(0)RBD3, -C(O)ORB03,- and - C(0)NRBD3Re°4; and R60 , RM5 and R60 are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the R6A and RSB heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, hydroxy, alky), hydroxyalkyl, alkylcarboxyalkyl, carboxyalkyl, and amlnocarbony!.

In another embodiment, the R6A and R6B heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, -OH, -CH3l - CH2CH3, -CH2CH2CH3, -CHiCHjCHiCHs, *CH(CH3)CH3, -C(CH3)2CH3, -C(CH3)3, -CH2.OH1 - CH2CH2OH, -CHsCHsCHjtOH, -CH2CH(CH3)OH, -CH(CH3)CH(CH3)OH, - CH2C(CH3)2OH, - CH;C(0)OH, - CH:C(0)OC(CHj)3, and -C(0)NH2. In another embodiment, the R6A and ReB heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, -OH, -CH3, -CH2CH3, -CH2OH, -CHzCH2OH, -CH;CH:CH2OH, - CH2CH(CH3)OH, -CH2(CH3)CH(CH3)OH, and - CH2C(CH3):OH.

In another embodiment, the R6Aand RBB heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen and -CH2CHiOH. In another embodiment, the ReA and R8B heterocyclyl may be optionally substituted with one or more - CH2CH2OH.

Embodiments of ft6 Substituent In one embodiment of Formula I, Re is Ci to Ci0 alkyl, optionally substituted as provided in Formula I. In another embodiment of Formula I, R8 is C, to C8 alkyl, optionally substituted as provided in Formula I. In another embodiment of Formula I, Re is C, to Ce alkyl, optionally substituted as provided in Formula I. In another embodiment of Formula I, RB is C-, to C, alkyl, optionally substituted as provided in Formula I. In another embodiment of Formula I, R8 is ethyl, optionally substituted as provided in Formula I.

In one embodiment of Formula I, R8 is substituted with -OR801, wherein R901 is as provided in Formula I. In another embodiment of Formula I, R8 may be optionally substituted with one or more substituents independently selected from the group consisting of halogen and -OR801, wherein RB01 is selected from the group consisting of hydrogen and C to Ce alkyl, wherein (a) when the C-, to C6 alkyl is methyl, the methyl may be optionally substituted with 1 , 2, or 3 fluoro substituents, (b) when the C, to C5 alkyi comprises at least two carbon atoms, the a!kyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

In another embodiment of Formula I, Ret) is C2 to C« alky! optionally substituted with one or more substituents independently selecled from the group consisting of halogen, hydroxy, carboxy, alkoxy, haloalkyl , hydroxyalkyl, carboxyalkyl, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy. In another embodiment of Formula I , Re may be optionally substituted with one or more subslituents Independently selected from the group consisting of halogen, haloalkoxy, hydroxy, and alkoxy. In another embodiment of Formula I, Rfl may be optionally substituted with one or'more substituents independently selecled from the group consisting of haloalkoxy and alkoxy. In another embodiment of Formula I , Re Is ethyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, haloalkoxy, hydroxy, carboxy, and alkoxy. In another embodiment of Formula I, Rs is ethyl optionally substituted with one or more substituents independently selected from the group consisting of haloalkoxy and alkoxy.

In another embodiment of Formula I, Ra is alkyl substituted with -OR801 , wherein R801 is as provided in Formula I.

In another embodiment of Formula I, Rfl is alkoxyalkyl, optionally substituted as provided in Formula I.

In another embodiment of Formula I, R8 is a (d to C,)alkoxy(Ci to C,)alkyl; optionally substituted as provided in Formula I.

In another embodiment of Formula I, RB is methoxyethyl, as provided in Formula 1-13 in Table A. In another embodiment of Formula I, RB is ethoxyethyl, as provided In Formula 1-14 in Table A.

In another embodiment of Formula I, RB is propoxyethyl, as provided in Formula 1-15 in Table A.

In another embodiment of Formula I, R9 is trifluoroethylethoxy as provided in Formula 1-16 in Table A.

Additional Embodiments The-following are additional embodiments of the compounds of Formula I. Unless otherwise specified, substituents are as provided in Formula I. Further embodiments of Formula I provided when R2, R6A, R6B and R8 are selected from the various embodiments provided above.

Embodiments where R8 is alkyl substituted with -OR101, R2 is phenyl or 5 to 6 membered heteroaryl In one embodiment of Formula I, R2 is selected from the group consisting of phenyl and 5 to 6 membered ring heterocycyl, wherein ihe R2 phenyl and heterocyclyl may be optionally substituted as provided in Formula I, and RB is alkyl susbslilu!ed with -OR801, wherein R801 is as provided in Formula I.

In one embodiment of Formula I, R2 Is selected from the group consisting of phenyl and 5 to 6 membered ring heteroaryl, wherein the R2 phenyl and heteroaryl may be optionally substituted as provided in Formula I, and R9 is alkyl susbstltuted with -OR801 , wherein R801 Is as provided In Formula I. In another embodiment of Formula I, R1 is selected from the group consisting of phenyl and 5 to 6 membered ring heteroaryl, wherein the R2 phenyl and heterocyclyl may be optionally substituted as provided in Formula I, and R8 is alkox alkyl, wherein the R8 alkoxyalkyl may be opiionally substituted as provided in Formula J.

In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl, pyridinyl, and isoqulnolinyl wherein the R2 phenyl, thienyl, pyridinyl, and isoquinolinyl may be optionally substituted as provided In Formula I, and R8 is a (C, to C )alkoxy(C, to C^alkyl, wherein the Rs alkoxyalkyl may be optionally substituted as provided in Formula I.

In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl and pyridinyl, wherein the Rz phenyl, thienyl and pyridinyl may be optionally substituted as provided in Formula I, and Re is selected from the group consisting of methoxyethyl, ethoxyethyl, propoxyethyl, and trifluoroethoxyethyl.

In another embodiment of Formula I, R2 is selected from the group consisting of phenyl and pyridinyl, wherein the R2 phenyl and pyridinyl may be optionally substituted as provided in Formula I, and R8 is selected from the group consisting of methoxyethyl, ethoxyethyl, propoxyethyl, and !rifluoroethylethoxy.

In another embodiment of Formula I, R2 Is selected from the group consisting of phenyl and pyridinyl, wherein the R2 phenyl and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, methoxy, ethoxy, isopropoxy, hydroxy, hydroxymethyl, ethanone, dimethylamino and ethylsulfonyl and R6 is selected from the group consisting of methoxyelhyl, elhoxyethyl, propoxyethyl and triiluoroethyietnoxy.

In another embodiment of Formula I, R2 is selected from the group consisting of phenyl and pyridinyl, wherein the R2 phenyl and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, and methoxy and Re is selected from the group consisting of methoxyethyl, elhoxyethyl, and propoxyethyl.

In another embodiment of Formula I, R2 is pyridinyl, optionally substituted with methoxy, and R8 is propoxyethyl.

In another embodiment, R2 and Re are as provided in Formula 1-18 of Table A.

Embodiments where R6A and R6B together with the nitrogen to which they are attached form a partially or fully saturated 5 to 7 membered ring heterocyclyl and R8 Is alkyl substituted with - OR601 In one embodiment, R6 and R6B together with the nitrogen to which they are attached Is a partially or fully saturated 5 to 7 membered ring heterocyclyl, wherein the 5 to 7 membered ring heterocyclyl may be optionally substituted as provided in Formula I, and R8 is alkyl substituted with - OR801, wherein RM1 Is as provided in Formula I.

In another embodiment, ReA and R8B together with the nitrogen to which they are attached form a partially or fully saturated 5 to 7 membered ring heterocyclyl helerocyclyl selected from the group consisting of pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl; and diazapinyl, wh.erein the pyrrolidine, piperadinyl, piperazinyl, morpholinyl, and diazapinyl may be optionally substituted as provided in Formula I, and Re is alkyl substituted with -OR801, wherein RB01 Is as provided in Formula I.

In another embodiment, R6A and ReB together with the nitrogen to which they are attached form a partially or fully saturated 5 to 7 membered ring heterocyclyl heterocyclyl selected from the group consisting of piperadinyl, piperazinyl, and morpholinyl, wherein the piperadinyl, piperazinyl, and morpholinyl may be optionally substituted as provided in Formula I, and R* is alkyl substituted with -OR801, wherein RBtM is as provided in Formula I.

In another embodiment, R and R together with the nitrogen to which they are attached forms a piperadinyl optionally substituted as provided In Formula I, and Ra is alkyl substituted with -OR60', wherein R801 is as provided in Formula i.

In another embodiment, RSA and R6B together with the nitrogen to which they are attached forms a piperazinyl optionally substituted as provided in Formula I, and R8 is alkyl substituted with -ORB°\ wherein RBD1 is as provided in Formula I.

Embodiments where R2 is phenyl or 5 to 6 membered heteroaryl, ReA and R6B together with the nitrogen to which they are attached form a 5 to 7 membered fully saturated heterocyclyl, and R8 is alkyl substituted with -OR801 In one embodiment of Formula I, R1 is selected from the group consisting of phenyl and 5 to 6 membered ring heteroaryl, wherein the R2 phenyl and heteroaryl may be optionally substituted as provided in Formula I; R6A and R6B together with the nitrogen to which they are attached is B partially or fully saturated 5 to 7 membered ring heterocyclyl, wherein the 5 to 7 membered ring heterocyclyl may be optionally substituted as provided in Formula I; and R8 is alkyl susbstltuted with -OR801, wherein R801 is as provided in Formula I.

In another embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl, pyridinyl, and isoquinolinyl, wherein the R2 phenyl, !hienyl, pyridinyl, and isoquinolinyl may be optionally substituted as provided in Formula I; R6A and R6B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, and dlazapinyl, wherein the pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, and diazapinyl may be optionally substituted as provided In Formula I; and RB is alkyl susbstituted with -OR801, wherein R801 is as provided In Formula I.

Embodiments where R2 is phenyl, thienyl or pyridinyl, R6A and R6B together with the nitrogen to which they are attached form a partially of fully saturated 5 to 7 membered ring heterocyclyl, and R8 is alkyl substituted with -OR801 In one embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl, and pyridinyl, wherein the R2 phenyl, thienyl, and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, -OR™1, -C(0)R101, -C(0)ORzot, -NR201R202, and -S(0)2RM1 ; wherein said alkyl and alkenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(0)OR203; and WO 2007/122466 PCT/IB2OO7/O 1001 RZQI, R202 and R203 are independently selected from the group consisting of hydrogen and alkyl, wherein said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and alkoxy; R6A and R6B together with the nitrogen to which they are attached form a partially or fully saturated 5 to 7 membered ring heterocyclyl, wherein the 5 to 7 membered ring heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -ORB0\ -C(O)Re0\ - C{0)ORM1, -NR601Reoz, - N(Re01)C{O)Re02l and -CtOJNR^R602, wherein (a) said alkyl substituent may be optionally substituted with one or more substituent selected from the group consisting of halogen, -OR603, - C(0)R903, -C(O)ORe03,-NRe03R604, and -C(O)NR603R6W; and R50', RM2, R603 and R604 are independently selected from the group consisting of hydrogen and alkyl, wherein (a) said R80 and R602 alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxya!kynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxy alkoxy. and carboxyalkoxy; Re is alkyl substituted with -OR801; and R801 is selected from the group consisting of hydrogen and alkyl wherein (a) when said alkyl is methyl, said methyl may be optionally substituted with 1 , 2, or 3 fiuoro substituents, {b} when said alkyl comprises at least two carbon atoms, said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, and alkynyl.

In another embodiment, RB is d to C4 alkyl substituted with -Reo\ wherein R801 is C, to C4 alkyl optionally substituted with 1 , 2, or 3 fiuoro substitutents.

In another embodiment, R8 Is C, to C4 alkyl substituted with -RBD1, wherein RBD1 is d to Ct alkyl optionally substituted with 1 , 2, or 3 fiuoro substitutents and Rz is selected from the group consisting of phenyl, thienyl, and pyrldinyl, wherein the H∑ phenyl, thienyl, and pyridlnyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, alkyl, -OR20', -C(O)R20\ NR^R202, - and -S{0)2R2t> ; wherein said alkyl may be optionally substituted with one or more -OR203, and R201, R201 and R203 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, the R2 phenyl, thienyl, and pyridlnyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, chloro, fiuoro, methyl, methoxy, ethoxy, hydroxymethyl, -C(0)CH3, -C(0)CH(CH3)2l -N(CH3)2> and -S(0)aCHa (CH3).

In another embodiment, Re is C, to C, alkyl substituted with -R801', wherein RB01 is C, to C» alkyl optionally substituted with 1 , 2, or 3 fluoro substltutents and R6A and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadlnyl, piperazinyl, morpholinyl, and diazapinyl, wherein the pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, and diazapinyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, -OR601, and -C(0)NReo,R602, wherein said a!kyl substituent may be optionally substituted with one or more substltuent selected from the group consisting of -ORB03, -C(O)ORe03, and -NRB03Rec4; and RBD1, Reo2, RE03 and R604 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, R8 ' is C, to C, alkyl substituted with -Rao\ wherein Re01 is C, to C alkyl optionally substituted with 1 , 2, or 3 fluoro substltutents and Rw and RflB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl and morpholinyl wherein the piperadinyl, piperazlnyl and morpholinyl may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C{CH3):NH2, -CH{CH3)CH(CH3)NH2, - CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, -CHzC(0)OH, and -C<0)NH2. In another embodiment, Re is d to Ct alkyl substituted with -Raoi, wherein Rfl01 is Ci to C, alkyl optionally substituted with 1 , 2, or' 3 fluoro substltutents and R6A and R6B together with the nitrogen to which they are attached form a . piperazinyl wherein the piperazinyl may be optionally substituted with one or more substituents Independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH<CH3)CH<CH3)NH2, - CH2CH(CH3)OH, -CH2C{0)OC(CH3)3, -CH.C(0)OH, and -C(0)NH2.

In another embodiment, Re Is C, to C4 alkyl substituted with -R801, wherein R801 is Ci to Cj alkyl optionally substituted with 1 , 2, or 3 fluoro substltutents; R2 Is selected from the group consisting of phenyl and pyridinyf, wherein the phenyl and pyridlnyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, fluoro, methyl, methoxy, ethoxy, hydroxymethyl, -C(0)CH3, -C{0)CH(CH3)2l -N<CH3)2l and -S<0)2CH_(CH3), and R6A and Ree together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadlnyl, piperazinyl, and morpholinyl wherein the plperadinyl, piperazinyl, ■ and morpholinyl may be optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2) -CH{CH3)CH(CH3)NH2, -CH2CH(CH3)OH, -CH2C(0)OC{CH3)3, -CH2C(OJOH, and -C(0)NH2.

In another embodiment, R2 is pyr!dinyl substituted with methoxy; R6A and ReB together with the nitrogen to which they are attached form a piperazinyl, optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH{CH3)CH(CH3)NH2, -CH2CH(CH3)OH, - CH2C(0)OC(CH3)3, -CH2C(O)0H, and -C(0)NH2; and Ra Is propoxyethyl.

Embodiments where R2 is phenyl, thienyl or pyridlnyl, ReA and R6B together with the nitrogen to which they are attached form a pyrrolidinyl, piperadinyl, piperazinyl or morpholino, and R8 is a!kyl substituted with -ORB01 In one embodiment of Formula I, R2 is selected from the group consisting of phenyl, thienyl, and pyridlnyl, wherein the R2 phenyl, thienyl, and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, -OR201, -C(O)R20\ -C(0)OR201, -NR201R °2, and -S(0)2R2°1; wherein said alkyl and alkenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(0)OR203; and R201, R202 and R203 are Independently selected from the group consisting of hydrogen and alkyl, wherein said aikyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and alkoxy; RflAand ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyf, piperazinyl, morpholinyl, and dlazapinyl, wherein the pyrrolidinyl, piperadinyl, plperazinyi, morpholinyl, and diazapinyi may be optionally substituted with one or more substituents Independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -OR80', -C(O)R60\ - C{0)OR601, -NR601Re02( - N(RBt)1)C(0)Re°2, and -C(0)NReD1RBM, wherein said alkyl substituent may be optionally substituted with one or more substituent selected from the group consisting of halogen, -OR803, -C(0)ReM, - C(O)OR603,-NRe03R604, and -C(O)NR60 RBM; and R601, R602, R603 and Rew are independently selected from the group consisting of hydrogen and alkyl, wherein (a) said Re01 and R602 alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

R8 is alkyl substituted with -OR"01; and Ri01 Is selected from the group consisting of hydrogen and alkyl wherein (a) when said alkyl is methyl, said methyl may be optionally substituted with 1, 2, or 3 fluoro substituents, (b) when said alkyi comprises at least two carbon atoms, said alkyl may be optionally substituted with one or more substituents independently selecled from the group consisting of halogen, hydroxy, carboxy, oxo, and alkynyl.

In another embodiment, Re is C, to C« alkyl substituted with -Raoi, wherein RB01 is C1 to C4 alkyl optionally substituted with 1, 2, or 3 fluoro substitutents. In another embodiment, R8 is C, to C alkyl substituted with -R , wherein R is to C alky) optionally substituted withl , 2, or 3 fluoro substilutents and R6A and R6B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl, and morpholinyl, wherein the piperadinyl, piperazinyl, and morpholinyl may be optionally substituted as provided above. In another embodiment, Re is C¾ to C4 alkyl substituted with -RB01, wherein RB01 Is C, to C alkyl optionally substituted with 1 , 2, or 3 fluoro substitutenls; Rz is selected from the group consisting of phenyl and pyridlnyl, wherein the R2 phenyl and pyrldinyl may be optionally substituted as provided above, and R6A and RBB together with the nitrogen to which they are attached form a heterocyclyl ■ selected from the group consisting of piperadinyl, piperazinyl, and morpholinyl, wherein the piperadinyl, piperazinyl, and morpholinyl may be optionally substituted as provided above. In another embodiment, R8 is Ci to C* alkyl substituted with -RSD , wherein RM1 is C, to C, alkyl optionally substituted with 1 , 2, or 3 fluoro substitutenls; RJ is phenyl, wherein the phenyl may be optionally substituted as provided above, and RBA and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl and piperazinyl, wherein the piperadinyl and plperazlnyl may be optionally substituted as provided above. In. another embodiment; RB is Ci to C, alkyl substituted with -R80\ wherein R80 is Ci to C alkyl optionally substituted with 1. 2, or 3 fluoro substitutenls; Rz is phenyl, optionally substituted as provided above, and RGA and RflB together with the nilrogen to which they are attached form a piperadinyl wherein the piperadinyl may be optionally substituted as provided above.

In another embodiment, R8 is C, to C4 alkyl substituted with -RB0\ wherein R801 is C, to C alkyl optionally substituted with 1 , 2, or 3 fluoro substilutents; R2 is pyridlnyl, wherein the pyrldinyl may be optionally substituted as provided above, and R6A and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl and piperazinyl, wherein the piperadinyl and piperazinyl may be optionally substituted as provided above.

In another embodiment, R8 Is to C4 alkyl substituted with -R80 , wherein R801 is C, to C4 alkyl optionally substituted with 1 , 2, or 3 fluoro substitutents; R2 is pyridinyl, wherein the pyridinyl may be optionally substituted as provided above, and ReA and R6B together with the nitrogen to which they are attached form a piperazinyl wherein the piperazinyl may be optionally substituted as provided above.

In another embodiment, Re is Ct to CA alkyl substituted with -RBD\ wherein R801 is C, to C4 alkyl optionally substituted with 1 , 2, or 3 fluoro substitutents; R2 is pyridinyl, wherein the pyridlnyl may be optionally substituted as provided above, and R6A and R6B together with (he nitrogen to which they are attached form a piperadinyl wherein the piperadinyl may be optionally substituted as provided above.

In another embodiment, Ra Is C, to C, alky I substituted with -R801, wherein ReD is C, to C, alkyl optionally substituted with 1, 2, or 3 fluoro substitulents; R2 is selected from the group consisting of phenyl, thienyl and pyridinyt, wherein the R2 phenyl, thienyl and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, alkyl, -OR!01, -NR2D,R202, abd S(0)2R201; wherein said. alkyl may be optionally substituted with one or more -OR203; and R20\ R202, and R201 are independently selected from the group consisting of hydrogen and alkyl. In another embodiment, Ra is d to C. alkyl substituted with -Reo\ wherein R801 is C, to d alkyl optionally substituted with 1 , 2, or 3 fluoro substitulents; R2 is selected from the group consisting of phenyl, thienyl and pyridinyl, wherein the R2 phenyl, thienyl and pyridinyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, chloro, fluoro, methyl, methoxy, ethoxy, hydroxymethyl, -C(0)CH3, -C{0)CH(CH3)2, -N(CH3)2 and -S(0)2CH2(CH3).

In another embodiment, R8 is C, to C' alkyl substituted with -R80 , wherein R801 Is d to alkyl optionally substituted with 1 , 2, or 3 fluoro substitutents; R6A and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyl, plperazinyl, morpholinyl, and dlazapinyl, wherein the pyrrolidinyl, piperadinyl, plperazinyl, morpholinyl, and diazapinyl may be optionally substituted with one or more substituents · independently selected from the group consisting of hydrogen, halogen, alkyl, -OR601, and -C(0)N RM1Re02, wherein said alkyl substituted may be may be optionally substituted with one or more substituent selected from the group consisting of -OR803, -C(0)ORew,and -NR^R80', and R60 , R602, R803, and Rwd are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, Re is to alkyl substituted with -R801, wherein R-801 is d to alkyl optionally substituted with 1 , 2, or 3 fluoro substitutents; ReA and R6B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyl, piperazinyJ, morpholinyl, and diazapinyl/ wherein the pyrrolidinyl, piperadinyl, plperazinyl, morpholinyl, and diazapinyl may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3)CH(CH3)NH2, -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, -CH2C(0)OH, and -C(0)NH2.

In another embodiment, R2 is selected from the group consisting of phenyl and pyridinyl, wherein the phenyl and pyridinyl may be optionally substituted with one or more subsitutents selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, -OR201, -C(0)R201, -C(0)OR201, -NR20,R202, and -S(0)2R201; wherein said alkyl and alkenyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, - O !M, and -C(O)OR:03; and R20i, R2qt and R203 are independently selected from the group consisting of hydrogen and alkyl, wherein said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy and alkoxy; R6A and REB together with the nitrogen to which they are attached form a heterocyciyl selected from the group consisting of piperadinyl, piperazinyl, and morphoiinyl wherein the piperadinyl, piperazinyl, and morphoiinyl may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -OR601, -C(0)Reo\ - ' C(0)OR60\ -NRC01 Re02, -N(Re0 )C(O)R602, and -C(O)NRB0 R602, wherein (a) said a!kyl substituent may be optionally substituted with one or more substituents selected from the group consisting of halogen, -OR603, -C(O)Re03, -C(0)OR603, and -NR603R6M; and Ret", R602, Reo3 and Rew are independently selected from the group consisting of hydrogen and alkyl, wherein (a) said Re01 and R602 alkyl may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

In another embodiment, R2 is selected from the group consisting of phenyl and pyridinyl, wherein the phenyl and pyridinyl may be optionally substituted with hydroxy, halogen, alkyl, -OR2"1, - NRS01Rara, - and -S(O)2R!01; wherein said alkyl may be optionally substituted with one or more -OR203; R201, R2M and R203 are independently selected from the group consisting of hydrogen and alkyl; R6Aand RflB together with the nitrogen to which they are attached form a heterocyciyl selected from the group consisting of piperadinyl, piperazlnyl, and morphoiinyl wherein the piperadinyl, piperazlnyl, and morphoiinyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, -OR801, and -C(O) RBD1RB02, wherein said alkyl substituent may be optionally substituted with one or more substituent selected from the. group consisting of -OR603, -C(0)OReM, and -NR603Re04; and R601, R602, R603 and R604 are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, R8 is Ci to C, alky! substituted with -R801, wherein R601 Is C, to C4 alkyl optionally substituted with 1 , 2, or 3 fluoro substltutents; R2 Is selected from the group consisting of phenyl and pyridinyl, wherein t e phenyl and pyridinyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, fiuoro, methyl, methoxy, ethoxy, hydroxymethyl, -C(0)CH3, -C(0)CH(CH3)2, -N(CH3)2l and -S(0)2CH2{CH3), and RSA and R6B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl, and morpho!inyl wherein the piperadinyl, piperazinyl, and morpholinyl may be optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3}CH(CH3)NH2l -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, - CH2C(0)OH, and -C{0)NH2.

In another embodiment, 8 Js ethyl substituted with -R801, wherein R801 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl wherein said methyl, ethyl and propyl may be optionally substituted with 1 , 2 or 3 fiuoro substituents; R2 is selected from the group consisting of phenyl and pyrldinyl, wherein the phenyl and pyridinyl may be optionally substituted with one or more substituents selected from the group consisting of hydroxy, chloro, fiuoro, methyl, methoxy, ethoxy, hydroxymethyl, -C<0)CH3, .C(0)CH(CH3)2t -N(CH3)2, and -S(0)2CH2(CH3), and RBA and R6B together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl, and morpholinyl wherein the piperadinyl, piperazinyl, and morpholinyl may be optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2l -CH(CH3)CH{CH3)NH2, -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, -CHzC(0)OH, and -C(0)NH2.

In another embodiment, R2 is pyrldinyl substituted with methoxy, and ReA and R8B together with the nitrogen to which they are attached form a piperazinyl, wherein the piperazinyl may be optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C{CH3)INH2, -CH(CH3)CH{CH3)NH2, -CH2CH(CH3JOH, -CH2C(0)OC(CHj)3, -CH2C(0)OH, and -C{0}NH2; and RB is propoxyethyl.

Embodiments of Formula 1-12 In one embodiment, the invention comprises compounds having the structure of Formula 1-12 of Table A : wherein: R2 Is pyrldiny!, optionally substituted with one or more substituents Independently selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, alkenyl, alkynyl, cycloalkyi, -OR201, - C<0)R2D\ -OC(0)RZD1,-C(0)OR201, -NR201R202, -N(R202)C(O)R2M, -C(O)NR201R202, - C(O)NR201C(O)R202and -S(0)zR; wherein said alkyl, alkenyl, and alkynyl and cycloalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, oxo, -OR203, and -C(0)OR203; RM1, R202 and R203 are independently selected from the group consisting of hydrogen and alkyl, wherein said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, alkoxy, carboxy and -C{0)NH2,' ReAand R6B together with the nitrogen to which they are attached form a 5 to 7 membered partially or fully saturated ring heterocyclyl, wherein the heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, oxo, alkyl, alkenyl, alkynyl, cyano, -OR601, -NRe0 R602, -N(R6D,)C(0)Rew, -C(O)NRe01R602, -C(O)NRe01C(O)R602, cycloalkyi, aryl, and heterocyclyl, wherein (a) said alkyl, alkoxy, alkylamino, alkylcerbonyl, alkenyl, alkynyl and cycloalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, -OR903, -C(O)Re03, -C(0)ORew, -OC(O)Re03„ -NRe03Re(M, - N(Re03)C(O)ReM, -C(O)NR603Rfl0\ -C(O)NR803C(O)Re04, -SRe03,-S(O)Re03, -S(0)2Rem, - N(ReD3)S(O)2Re04, and -S(<%NRTO3Re04, C(O)NRet, C(O)Re04, -SR603, -S(O)Re03, -S(O)2Re03, - N(RB03)S(O)zRe04, and -S(0)2NReo3Reo\ and (b) said Re ary) and heterocyclyl substituents may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cyano, oxo, -OR601, -C(O)RB0\ -C(0)OReD\ -OC(O)Rfl0\ -NRe01Rea2, -N(RS01)C(0)RW!, -C(O)NRe0,Re02, -C(O)NRe01C(O)Re02, -SReo\ -S(O)Re02, -S(0)2R601, -N(R601)S(O)2Re02, and -S(O)2NRe01R802; R601, Re02, R803 and R6W are independently selected from the group consisting of hydrogen, alkyl, alkenyl, and alkynyl, wherein (a) said R601 and R602 alkyl may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy, and (b) said RBD, and R802 alkenyl and alkynyl substituents may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy; and R80 is selected from the group consisting of hydrogen, and methyl, ethyl and propyl, wherein said methyl, ethyl and propyl may be optionally substituted with 1 , 2, or 3 fluoro substituents.

In another embodiment of Formula 1-12, R2 is pyrldinyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, alkyl, -OR201, - C(0)R201, NR201R202, - and -S(0)2R201; wherein said alkyl may be optionally substituted with one or more -OR203, and R20 , R!M and R203 are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment of. Formula 1-12, R2 Is pyrldinyl optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, hydroxymethy!, hydroxyethyl, -C(0)C(CH3)z, -C(0)CH3l -N(CH3)Zl and - S(0)2CH2(CH3).

In another embodiment of Formula 1-12, the R^ pyrldinyl Is selected from the group consisting of , wherein RB, R10, R11, and R13 are Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, hydroxyaikyi, aminoalkyi, alkoxy, alkoxyalkyi, amino, alkylamino, aminosulfonyl, and aikylsulfonyl.

In another embodiment of Formula 1-12, the R pyridinyl has the structure , wherein Re, R10, R11, and R13 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, hydroxyaikyi, aminoalkyi, alkoxy, alkoxyalkyi, amino, alkylamino, aminosulfonyl, and aikylsulfonyl.

In another embodiment of Formula 1-12, the pyridlnyt has the structure , wherein Rs, R10, R11, and R13 are independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, melhoxy, ethoxy, hydroxymethyl, hydroxyethyl, -C(0)CH3, -C(0)CH(CH3)2, -N(CH3)2, and -S(0)2CHz(CH3).

In another embodiment of Formula 1-12, the R2 pyrldinyl has the structure wherein at least one of RB, R10, R11, and R13 are independently selected from the group consisting of chloro, fluoro, hydroxy, methyl, methoxy, ethoxy, hydroxymethyl, -C(0)CHa, -C(0)CH(CH3)2, - N(CH3)2, and -S(0)2CH2{CH3).

In another embodiment of Formula (-12, the R2 pyridlnyl has the structure wherein Re, R10 and R13 are each hydrogen, and R11 is selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, melhoxy, ethoxy, hydroxymethyl, hydroxyethyl, C(0)CH3, -C{0)CH(CH3)2, -N(CH3)2, and -S(0)2CH2(CH3).

In another embodiment of Formula 1-12, the R pyrldinyl has the structure wherein RB, R 0 and R13 are each hydrogen, and R11 is selected from the group consisting of hydrogen, methyl, methoxy, and -N{CH3)2.

In another embodiment of Formula 1-12, the R pyridlnyl has the structure , wherein Re, R10 and R13 are each hydrogen, and Rt1 is methoxy.

In another embodiment of Formula 1-12, Rz pyridinyl has the structure wh are each hydrogen, and R11 Is selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, - C(0)CH3, -C(0)CH(CH3)2, -N(CH3)2, and -S(0)2CH2(CH3); Rw and RBB together with the nitrogen to which they are attached form a 5 to 7 membered partially or fully saturated ring heterocyclyi, wherein the heterocyclyi may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -OR801, -CiOJR601, - C(0)OReo\ - NReD1R6-2, .N R^qOR'02, and -CfOJNR^ 802, wherein {a} said alkyl substituent may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, -OR603, -C{0)ReD3, -C{O)ORe03, and -NReo R6M; and Reo\ R602, R603 and R6W are independently selected from the group consisting of hydrogen and alkyl, wherein said R601 and R602 alkyl may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

In another embodiment of Formula 1-12, the R2 pyridlnyl has the structure , wherein RB, R10, R11, and R13 are Independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, -C(0)CH3l -C(0)CH(CH3)ip -N(CH3)2, and -S(0)2CH2(CHS); R6A and R6B together with the nitrogen to which they are attached form a 5 to 7 membered partially or fully saturated ring helerocyclyl, wherein the heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, alkyl, -OR601 , and - C(O)NR601R602, and R80 , Rsm, RM3 and Rm are independently selected from the group consisting of hydrogen and alkyl.

. In another embodiment of Formula 1-12, the R2 pyrldinyl has the structure and R13 are independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethy!, hydroxyethyl, -C(0)CH3, -C(0)CH(CH3)2, -N(CH3)2, and -S{0)2CH2(CH3); RflAand ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group■consisting of pyrrolidinyl, piperadinyl, piperazlnyl, morpholinyl and diazapinyl, wherein the pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl and diazapinyl may be optionally substituted with one or more substituents selected from the group consisting of chloro, hydroxy, methyl, ethyl, propyl, hydroxymethyl, ' hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3)CH(CH3)NH::, -CH2CH(CH3)OH, -■ CH_C(0)OC(CH3)3, -CHzC(0)OH, and -C(0)NH2.

In another embodiment of Formula 1-12, the R2 pyridinyl has the structure , wherein R", R10, R11, and R13 are independently selected from the group consisting of hydrogen, chloro, fluoro, hydroxy, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, -C{0)CH3. -C{0)CH(CH3)2, -N(CH3)2, and -S(0)2CH2(CH3); ReAand R6B together with the nitrogen to which they are attached form a. heterocyclyl selected from the group consisting of pyrrolidinyl, piperadinyl, plperazinyl, morpholinyl, and diBzapinyl, wherein the pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, and diazapinyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, cyano, oxo, alkyl, -OReD1 , -C(0)R601, - C(0)OReo', -NR^R802, -N{Rw,)C(O)Re02, and -CfOJNR^R602, wherein <a) said alkyl substituent may be optionally substituted with one or more substituents Independently selected from (he group consisting of halogen, -OR603, -C(0)ReM, -C(0)OR6M, and -NRe03RBW; and ReD1, R602, R603 and R are independently selected from the group consisting of hydrogen and alkyi, wherein {a) said Rfl01 and R602 alkyi may be optionally substituted with one or more substltuents Independently selected from the group consisting of halogen, cyano, hydroxy, carboxy, oxo, alkynyl, haloalkynyl, hydroxyalkynyl, carboxyalkynyl, alkoxy, haloalkoxy, hydroxyalkoxy, and carboxyalkoxy.

In another embodiment of Formula 1-12, the Rz pyridlnyl may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, alkyi, -OR201, -C(O)R20\ NRm Rz02, - and -SfOfeR801; wherein said alkyi may be optionally substituted with one or more -OR203, and R201, R202 and R203 are independently selected from the group consisting of hydrogen and alkyi; ReA and ReB together with the nitrogen to which they are attached form a heterocyciyl selected from the group consisting of pyrrolidinyl, piperadinyl, piperazinyi, morpholiny!, and diazaplnyl,, wherein the pyrrolidinyl, piperadinyl, piperazinyi, morphollnyl, and diazaplnyl may be optionally substituted with one or more substituents Independently selected from the group consisting of halogen, alkyi, -ORM1, and *C(O)NRe01R6C2, wherein (a) said alkyi substituent may be optionally substituted with one or more substituents independently selected from the group consisting of -OR803, -C(0)OReM, and -NReo3Rsw; and Reo\ R602, RB03 and R604 are independently selected from the group consisting of hydrogen and alkyi.

In another embodiment of Formula 1-12, the R2 pyridlnyl may be optionally substituted with one or more substituents independently selected from (he group consisting of hydroxy, chloro, f!uoro, methyl, ethyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, -C(0)CH3, -C(0)CH{CH3)2, -N(CHa)z, and -S(0)-CH2(CH3); ReAand ReB together with the nitrogen to which they are attached form a ' heterocyciyl selected from the group consisting of pyrrolidinyl, piperadinyl, piperazinyi, morpholinyf, and diazaplnyl,, wherein the pyrrolidinyl, piperadinyl, piperazinyi, morphollnyl, and diazaplnyl may be optionally substituted with one or more substituents independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3)CH(CH_)NH2, -CH2CH(CH3)OH, -CH2C{0)OC(CH3)3, -CH2C(0)OH, and -C(0)NH2.

In another embodiment of Formula 1-12, the Rz pyridlnyl is selected from the group consisting of Independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyi, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, amino, alkylamino, aminosulfonyl, and alkylsulfonyl; R and R together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadlny/, piperazlnyl and morpholinyl wherein the piperadinyl, piperazinyl and morpholinyl may be optionally substituted with one or more substituenls Independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, propyl, hydroxym ethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3)CH(CH3)NH2, -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3l - CH2C(0)OH, and -C(0)NH2.

In another embodiment of Formula 1-12, the Rz pyrldlnyi has the structure , wherein Rs, R'° and R 3 are each hydrogen; R11 is selected from the group consisting of hydrogen, hydroxy, chloro, fluoro, methyl, -ethyl, methoxy, ethoxy, hydroxym ethyl, hydroxyethyl, -C{0)CH3, -C(0)CH(CH3)2, -N(CH3)2, and -S(0)2CH2(CH3); R6Aand Re together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl and morpholinyl wherein the piperadinyl, piperazinyl and morpholinyl may be optionally substituted with one or more substituenls independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl; - CH2C(CH3)2NH2, -CH(CH3)CH{CH3)NH2l -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, -CH2C(O)0H, and - . C{0)NH2; and R801 Is propyl.

In another embodiment of Formula 1-12, the R2 pyridinyl has the structure , wherein one of Re, R10, R11 and R 3 is methoxy and the remainder of Re, R10, R11 and R13 are hydrogen; R6A and ReB together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of piperadinyl, piperazinyl and morpholinyl wherein the piperadinyl, piperazlnyl and morpholinyl may be optionally substituted with one or more substituents Independently selected from the group consisting of chloro, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C{CH3)2NH2, -CH(CH3)CH(CH3)NH2, -CH2CH(CH3)OH, -CH2C(0)OC(CH3)3, -CH2C(0)OH, and -C(O)NHZ; and R801 Is propyl.

In another embodiment of Formula 1-12, the R2 pyridlnyl has the structure , wherein one of Re, R10, R11 and R13 is methoxy and the remainder of R8, R 0, R11 and R13 are hydrogen; RflAand RBB together with the nitrogen to which they are attached form a piperazinyl wherein the piperazinyl may be optionally substituted with one or more substituents independently selected from the group consisting of chioro, hydroxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CHj>C(CH3)2NH2, -CH(CH3)CH{CH3)NH2[ - CH_CH(CH3)OH, -CH2C(0)OC(CH3)3, -CH2C(0)OH, and -C(0)NH_.

In another embodiment of Formula 1-12, the R2 pyridinyl has the structure , wherein one of R9, R10, R11 and R13 is methoxy and the remainder of RB, R10, R11 and R13 are hydrogen; R6Aand ReB together with the nitrogen to which they are attached form a piperazinyl wherein the piperazinyl may be optionally substituted with one or more substituents Independently selected from the group consisting of methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CH2C(CH3)2NH2, -CH(CH3)CH{CH3)NH2, - CH2CH(CH3)OH( -CH2C(0)OC(CHa)3, and -CH2C(O)0H.

C. Isomers When an asymmetric center is present In a compound of Formulae (I) through (I-32) the compound can exist In the form of enantiomers or diastereomers. In one embodiment, the present invention comprises enantiomeric forms and mixtures, including racemic mixtures of the compounds of Formulae (I) through (I-32). In another embodiment, the present invention comprises diastereomeric forms {individual diastereomers and mixtures thereof) of -compounds of Formulae \) through (I-32). When a compound of Formulae (I) through (I-32) contains an alkenyl group or moiety, geometric isomers may arise.

D, Tautomeric Forms The present invention comprises the tautomeric forms of•compounds of Formulae (I) through (I-32). For instance, a lautomeric form of the following compound: may be represented by: The various ratios of the tautomers In solid and liquid form is dependent on the various substiluents on the molecule as well as the particular crystallization technique used to isolate a compound.

E. Salts The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability In differing temperatures and humidities, or a desirable solubility in water or oil. In some Instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

Where a salt Is Intended to be administered to a patient (as opposed to, for example, being used in an In vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compognd of Formulae (I) - (1-32) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible Include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonlc, benzoic, citric, ethanesulfonic, fumarlc, gluconic, glyco!lc, Isothionlc, lactic, lactoblonic, maleic, malic, methanesulfonic, (rifluoromethanesulfonic, succinic, (oluenesulfonlc, tartaric, and trifiuoroacelic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, eraliphatic, heterocyclyl, carboxyic, and sulfonic classes of organic acids.

Specific examples of suitable organic acids include acetate, trlfluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleale, fumarate, pyruvate, aspartate, glutamate, benzoale, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonale (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesuironate, sufanilate, cyclohexylamlnosulfonate, algenic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotlnate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thlocyanate, and undecanoate.

In another embodiment, examples of suitable addition salts formed include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsyate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloridefchloride, hydrobromlde/bromide, hydrolodide/lodlde, isethlonate, lactate, ' malate, maleate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihldrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

In another embodiment, representative salts include benzenesulfonate, hydrobromlde'and hydrochloride.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium' . salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic llgands, e.g., quaternary ammonium salts.

In another embodiment, base salts are formed from bases which form non-toxic salts, Including aluminum, arglnine, benzathine, choline, dlethylamlne, diolamine, glycine, lysine, meglumine, olamine, tromethamine'and zinc salts.

Organic salts may be made from secondary, tertiary or quaternary amine salts, such as (romethamine, dlethylamlne, Ν,Ν'-dibenzylethylenedlamine, chloroprocalne, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamlne), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C^ to Ce) halldes (e.g., methyl, ethyl, propyl, -and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g. , dimethyl, diethyl, dibuytl, and diarnyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyi halides (e.g., benzyl and phenethyl bromides), and others.

In one embodiment, salts of the compounds of this Invention include hydrochloric acid (HCI) salts, trifluoroacetate (CF3COOH or "TFA") salts, mesylate salts, and tosylate salts.

Pharmaceutically acceptable salts of compounds of Formulae {I) to (1-32) may be prepared by one or more of three methods: (1) by reacting the compound of any one of Formulae (I)- (1-32) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of Formulae (I)- (1-32) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; and (III) by converting one sait of the a compound of Formulae (I) through (1-32) to another by reaction with an appropriate add or base or by means of a suitable ion exchange column. All three reactions are typically carried out fn solution. The resulting salt may precipitate out and be coDected by filtration or may be recovered by evaporation of the solvent, The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionised.

F, Methods of Treatment The present invention further comprises methods for treating a condition In a subject having or susceptible to having such a condition, by administering to the subject a therapeutically-effective amount of one or more compounds of. Formulae (I) through1 (1-32) as provided above, In one embodiment, the treatment Is preventative treatment, in another embodiment, the treatment Is palliative treatment. In another embodiment, the treatment is restorative treatment, In another embodiment, the condition is a PDE5-mediated condition. In another embodiment, the condition is a cGMP-mediated condition. A condition in which, for instance, insufficient cGMP is a major component, and whose production or action is modulated in response to the PDE5 enzyme, would therefore be considered a disorder mediated by cGMP.

The conditions that can be treated In accordance with the present invention Include, but are not limited to, cardiovascular conditions, metabolic conditions, central nervous system conditions, pufmonary conditions, sexual dysfunction, pain and renal dysfunction.

In another embodiment, the condition is a cardiovascular condition selected from the group consisting of hypertension (including essential hypertension, pulmonary hypertension, pulmonary arterial hypertension, secondary hypertension, Isolated systoiic hypertension, hypertension associated with diabetes, hypertension associated with atherosclerosis, and renovascular hypertension); complications associated with hypertension (including vascular organ damage, congestive heart failure, angina, stroke, glaucoma and impaired renal function); valvular insufficiency; stable, unstable and variant {Prinzmetal) angina; peripheral vascular disease; myocardial Infarct; stroke (including stroke recovery); thromboembolic disease; restenosis; arteriosclerosis; atherosclerosis; angiostenosis after bypass; angioplasty (Including percutaneous transluminal angioplasty and percutaneous transluminal coronary angioplasty); hyperllpidemia; hypoxic vasoconstriction; vasculitis (Including Kawasaki's syndrome); heart failure (Including congestive heart failure, decompensated heart failure, systolic heart failure, diastolic heart failure, left ventricular heart failure, right ventricular heart failure, and left ventricular hypertrophy); Raynaud's phenomenon; preeclampsia; pregnancy-induced high blood pressure; cardiomyopathy; and arterial occlusive disorders.

In another embodiment, the condition Is hypertension.

In another embodiment, the condition is pulmonary hypertension.

In another embodiment, the condition is pulmonary arterial hypertension.

In another embodiment, the condition is heart failure.

In another embodiment, the condition Is diastolic heart failure.

In another embodiment, the condition Is systolic heart failure.

In another embodiment, the condition is angina. in another embodiment, the condition is thrombosis.

In another embodiment, the condition is stroke.

In another embodiment, the condition is a condition associated with endothelial dysfunction (including conditions selected from the group consisting of atherosclerotic lesions, myocardial ischaemia, peripheral ischaemla, valvular insufficiency, pulmonary arterial hypertension, angina, clots, vascular complications after vascular bypass, vascular dilation, vascular repermeabilisalion, and heart transplantation).

In another embodiment, the condition is a metabolic condition selected from the group consisting of Syndrome X (also known as metabolic syndrome); diabetes (including type I and type II diabetes); Insulin resistance; syndromes of insulin resistance (including insulin receptor disorders, Rabson- Mendenhall syndrome, lepreohaunism, Kobberllng-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushlng syndrome, acromegaly, pheochomocytoma, glucagonoma, primary aldosteronism, somatostatlnoma, Lipoatrophic diabetes, -cell toxin induced diabetes, Grave's disease, Hashimoto's thyroiditis and idiopathic Addison's disease); impaired glucose tolerance; diabetic complications (including diabetic gangrene, diabetic arthropathy, diabetic nephropathy, diabetic glomerulosclerosis, diabetic deramatopathy, diabetic neuropathy, peripheral diabetic neuropathy, diabetic cataract, and diabetic retinopathy); hyperglycemia; and obesity.

In another embodiment, the condition is insulin resistance.

In another embodiment, the condition is nephropathy.

In another embodiment, the condition is a central nervous system condition selected from the group consisting of dementia, including vascular dementia and AIDS-induced dementia; spinal cord trauma, head trauma; traumatic brain injury; hypoglycemic neuronal damage; craniocerebral trauma; cerebral infarct; cerebrovascular accident; concentration disorders; chronic degenerative disorders, Including Alzheimer's disease; Parkinson's disease, Including Idiopathic and drug-induced Parkinson' disease; amyotrophic lateral sclerosis; amyolateral sclerosis; Huntington's disease, including Huntington's Chorea; muscular spasms and disorders associated with muscular spasticity Including tremors, epilepsy, convulsions; restless legs syndrome; multiple sclerosis; Creutzfeld- Jacob disease; sleep disorders, including narcolepsy; cognitive disorders, Including cognitive disorders relating to schizophrenia; psychosis, schizophrenia; substance withdrawal, including withdrawal from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics; anxiety, including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumattc stress disorder and obsessive compulsive disorder; attention deficlt/hyperactivlty disorder, conduct disorder; mood disorders,' Including depression, mania, bipolar disorders; trigeminal neuralgia, hearing loss, tinnitus, emesis, brain edema, tardive dyskinesia; and migraine, including migraine headache.

In another embodiment, the condition is Alzheimer's disease. )n another embodiment, the condition Is Parkinson's disease.

In another embodiment, the condition Is amyolateral sclerosis.

In another embodiment, the condition is cerebral infact.

In another embodiment, the condition is a concentration disorder.

In another embodiment, the condition Is stroke.

In another embodiment, the present invention further comprises methods for promoting functional recovery following brain injury. In another embodiment the present invention further comprises methods for promoting functional recovery following craniocerebral trauma, in another embodiment, the present invention further comprises methods for promoting functional recovery following stroke. (Ren, J.N., Finklestein, S.P., Tate, B., Stephenson, D.T., Seeger, T.F., and Menniti, F.S. The PDE5 inhibitor sildenafil improves functional recovery after middle cerebral artery occlusion In rats: mechanism of action? 582.15 Society for Neurosclence, 36th Annual Meeting 2006).

In another embodiment, the present Invention further comprises methods for promoting neurorestoration, Including neurorestoratlon following stroke, such as neurorestoration following coronary artery bypass grafting (CABG)-related stroke; neurorestoration following traumatic brain injury; neurorestoration following cerebral ischemia, including cerebral ischemia related to CABG; neurorestoration related to multl-lnfarct dementia; and neurorestoration related to post-CABG dementia.

In another embodiment, the condition is a concentration disorder.

. In another embodiment, the condition Is a pulmonary condition selected from the group consisting of asthma; acute respiratory distress; cystic fibrosis; chronic obstructive pulmonary disease; bronchitis; and chronic reversible pulmonary obstruction.

In another embodiment, the condition Is pain. In another embodiment, the condition is acute pain, Examples of acute pain Include acute pain associated with injury or surgery. In another embodiment, the condition Is chronic pain. Examples of chronic pain include neuropathic pain (Including postherpetic neuralgia and pain associated with peripheral, cancer or diabetic neuropathy), carpal tunnel syndrome, back pain (including pain associated with herniated or ruptured Intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinai muscles or the posterior longitudinal ligament), headache, cancer pain (including tumour related pain such as bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (including postc emotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome, pain associated with immunotherapy, or pain associated with hormonal therapy), arthritic pain (including osteoarthritis and rheumatoid arthritis pain), chronic post-surgical pain, post herpetic neuralgia, trigeminal neuralgia, HIV neuropathy, phantom limb pain, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord Injury, Parkinson's disease, epilepsy and vitamin deficiency. In another embodiment, the condition is nociceptive pain (including pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain), In another embodiment, the condition is pain associated with inflammation (including arthritic pain (such as osteoarthritis and rheumatoid disease pain), ankylosing spondylitis, visceral pain (including inflammatory bowel disease, functional bowel disorder, gastroesophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, Crohn's disease, ileitis, ulcerative colitis, dysmenorrhea!, cystitis, pancreatitis and pelvic pain). In another embodiment, the condition is pain resulting from musculoskeletal disorders (Including myalgia, fibromyalgia, spondylitis, sero-negative (non* rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis). In another embodiment, the condition is selected from the group consisting of heart and vascular pain (including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle Ischemia), in another embodiment, the condition Is selected from the group consisting of head pain (including migraine such as migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; orofacial pain, Including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain).

In another embodiment, the condition is sexual dysfunction (Including sexual dysfunction selected from the group consisting of impotence (organic or psychic); male erectile dysfunction; clitoral dysfunction; sexual dysfunction after spinal cord injury; female sexual arousal disorder; female sexual orgasmic dysfunction; female sexual pain disorder; and female hypoactive sexual desire disorder).

In another embodiment, the condition Is male erectile dysfunction.

In another embodiment, the condition is renal dysfunction (including renal dysfunction selected from the group consisting of acute renal failure, chronic renal failure; nephropathy (such as diabetic nephropathy); tubulointerslitia! disorders; glomerulopathy; and nephritis. In another embodiment, the condition is a cancer condition selected from the group consisting of cancerous cachexia; tumor metastasis and neoplasia.

In another embodiment, the condition is osteoporosis.

In another embodiment, the condition Is a gastrointestinal condition selected from the group consisting of nutcracker oesophagus; anal fissure; disorders of gut motility; irritable bowel syndrome, Crohn's disease and haemorrhoids, In another embodiment, the condition Is a urologlc condition selected from the group consisting of overactive bladder; bladder outlet obstruction; incontinence and benign prostatic hyperplasia.

In another embodiment, the condition is a skin condition, selected from psoriasis; urticaria and skin necrosis. in another embodiment, the condition is an ophthalmic condition selected from retinal disease; macular degeneration and glaucoma.

In another embodiment, the condition is nitrate intolerance.

In another embodiment, the condition is baldness. in another embodiment, the condition is a gynecologic condition selected from the group consisting of dysmenorrhoea (primary and secondary); infertility and premature labor. In another embodiment, the condition is secondary dysmenorrhoea.

In another embodiment, the present invention further comprises methods for Inducing weight loss or maintenance of weight loss In a subject by administering to the subject a therapeutically- effective amount of a compound of Formulae (I) through (1-32).

G. Subjects The methods and compounds of the present Invention are suitable for use with, for example, mammalian subjects such as humans, other primates (e.g., monkeys, chimpanzees), companion animals (e.g., dogs, cats, horses), farm animals (e.g., goats, sheep, pigs, cattle), laboratory animals (e.g., mice, rats), and wild and zoo animals (e.g., wolves, bears, deer). In one embodiment, the subject is a mammalian subject. In another embodiment, the subject Is a human.

H. Hypothesized Mechanism Without being held to a particular theory, it is hypothesized that compounds of Formulae (I) through (1-32) are inhibitors of the PDE5 enzyme, it is further hypothesized that the compounds of Formulae (I) through (1-32) inhibit the action of the PDE5 enzyme leading to an Increase in intracellular cGMP levels. This Increase in intracellular cGMP levels reduces intracellular calcium signaling, which in turn results in vascular smooth muscle relaxation and a reduction In blood pressure, I, Administration and Dosing Typically, a compound described in this specification is administered in an amount effective to inhibit PDE-5. The compounds of the present Invention are administered by any suitable route In the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.

The dosage regimen for the compounds and/or compositions containing the compounds Is based on a variety of factors, Including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful In the treatment of the above-Indicated conditions. In one embodiment, the total daily dose of a compound of Formulae (I) through {(-32) (administered in single or divided doses) is typically from about 0. 01 to about 100 mg/kg. In another embodiment, total dally dose of the compound of Formulae (I) through (IX) is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg {I.e., mg compound of Formulae (I) through (I-32) per kg body weight). In one embodiment, dosing Is from 0.01 to 10 mg/kg/day. in another embodiment, dosing is from 0.1 to 1.0 rng/kg/day. Dosage unit compositions may contain such amounts or submuttiples thereof to make up the dally dose, In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total dally dose, if desired.

For oral administration, the compositions may be provided in the form of tablets containing 0,01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1mg to about 00 mg of active Ingredient.

Intravenously, doses may range from about 0.1 to about 10 mg/kg/mlnute during a constant rate infusion.

J. Use In the Preparation of a Medicament In one embodiment, the present invention comprises the compounds of Formulae (I) through (I-32) for use as a medicament (such as a unit dosage tablet or unit dosage capsule). It is understood that the medicament may be in combination with one or more pharmaceutically-acceptable carriers and/or other active Ingredients.

In another embodiment, the invention comprises the use of one or more compounds of Formulae (I) through (1-32) for use as a medicament (such as a unit dosage tablet or unit dosage capsule) for use In treating one or. more of the conditions previously identified In the above sections discussing methods of treatment.

In another embodiment, the Invention comprises the use of one or more compounds of Formulae (I) through (1-32) in the preparation of a medicament for the treatment of hypertension.

K. Pharmaceutical Compositions For the treatment of the conditions referred to above, the compounds of Formulae (I) through (I- 32) can be administered as compound per se. Alternatively, pharmaceutically acceptable salts of the compounds of Formulae (I) through (1-32) can also be administered. In another embodiment, the compounds of Formulae (I) through (1-32) can be administered as a mixture of compound per se and one or more pharmaceutically acceptable salts of the compound per se.

In another embodiment, the present Invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise compounds of Formulae (I) through (1-32) presented with at least one pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the compounds of Formulae (I) through (1-32). Compounds of Formulae (I) through (1-32) may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.

The compounds of Formulae (I) through (1-32) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment Intended. The compounds and compositions of Formulae (I) through (I- 32), for example, may be administered orally, rectally, parenterally, or topically.

Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, the oral administration may be in a powder or granule form, In another embodiment, the oral dose form Is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of Formulae (I) through (1-32) are ordinarily combined with one or more adjuvants. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration Include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).

Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

In another embodiment, the present invention comprises a parenteral dose form. "Parenteral administration" Includes, for example, subcutaneous Injections, intravenous injections, Intraperitoneal^, intramuscular Injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.

In another embodiment, the present Invention comprises a topical dose form. "Topical administration" Includes, for example, transdermal administration, such as via transdermal patches or Iontophoresis devices, intraocular administration, or Intranasal or inhalation administration.

Compositions for topical administration also Include, for example, topical gels, sprays, ointments, and creams. A topical formulation may Include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention Is dissolved or suspended In suitable carrier. For intranasal administration or administration by inhalation, the compounds of Formulae (I) through (1-32) are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellent.

In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be In the form of, for example, a suppository.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures, The above considerations in regard to effective formulations and administration procedures are well known In the art and are described in standard textbooks. Formulation of drugs is discussed In, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co. , Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosaoe Porms. Marcei Decker, New York, N.Y., 1980; and KIbbe, et al., Eds., Handbook of Pharmaceutical Excipienls (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

L. Combinations and Combination Therapy · One or more compounds of the present invention can be used, alone or In combination with other therapeutic agents, in the treatment of various conditions or disease states discussed above. The compound(s) of the present invention and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or In separate dosage forms) or sequentially. Accordingly, in one embodiment, the present invention comprises methods for treating a condition in a subject having or susceptible to having such a condition by administering to the subject a therapeutically-effectlve amount of one or more compounds of Formulae (I) through (1-32) and one or more additional therapeutic agents. In another embodiment, trie present Invention comprises a pharmaceutical composition comprising one or more compounds of Formulae (I) through (1-32), one or more additional therapeutic agents, and a pharmaceutically acceptable carrier.

For instance, in one embodiment, one or more compounds of Formulae (1) through (i-32) may be administered with aspirin.

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more diruretlc. Examples of suitable diuretics Include hydroclorothlazide (such as ICROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™), bemetanlde (such as BU EX™), torsemide (such as DEMADEX™), metolazone (such as ZAROXOLYN™), chlorothiazide {such as DIURIL™, ESIDRIX™ or HYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such BS EDECRIN™), chlorthalidone (such as HYGROTON™), furosemide (such as LASIX™), indapamide (such as LOZOL™), or amiloride (such as MIDAMOR™ or MODURETIC™).

In one embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more angiotensin converting enzyme inhibitors. Examples of suitable angiotensin converting enzyme inhibitors Include quinapril (such as ACCUPRIL™), perindoprll (such as ACEON™), captopril (such as CAPOTEN™), enalaprtl (such as VASOTEC™), ENALAPR1LAT™. ramipril (such as ALTACE™), cilazaprii, delaprlt, fosenopril (such as MONOPRIL™), zofenoprll, indolaprll, benazepril (such as LOTENSIN™), llsinopril (such as PRINIVIL™ and ZESTRIL™), spiraprll, Irandolapril (such as MA 1K™}, perlndep, pentopril, moexiprl! (such as UNIVASC™)' fasldotril, S-allymercaptocaptopril, and plvopril.

In another embodiment, one or more compounds oF Formulae (I) through (1-32) may be coadministered with one or more angiotensin il receptor blockers. Examples of suitable angiotensin II receptor blockers Include candesartan (such as ATACAND™), eprosartan (such as TEVETEN™), irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan, olmesartan medoxomil (such as BENICAR™), tasosartan, telmlsartan (such as ICARDIS™), valsartan (such as DIOVAN™), zolasartan, FI-6828K, RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, and TA-606.

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more calcium channel blockers. Examples of suitable calcium channel blockers Include nifedipine (such as ADALAT™, ADALAT CC™ and PROCARDIA™), verapamil (such as CALAN™, COVERA-HS™, 1SOPTIN SR™ and VERELAN™), diltlazem (such as CARDIZEM™ CARDIZE CD™, CARDIZEM LA™, CARDIZEM SR™, D!LACOR™, TIAMATE™ and TIAZAC™ ), isradipine (such as DYNACIRC™ and DYNACIRC CR™), amlodiplne {such as NORVASC™), felodipine (such as PLENDIL™), nlsoldiplne (such as SULAR™), beprldll (such as VASCOR™), vatanidipina, clevldlplne, lercanldipine, dllltiazem, and NNC-55-0396.

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more beta blockers, Examples of suitable beta blockers include timolol (such as BLOCARDEN™), carteolol (such as CARTROL™), carvedlloi (such as COREG™), nadolol (such as CORGARD™), propranolol (such as INNOPRAN XL™), betaxolot (such as KERLONE™), penbutolol (such as LEVATOL™), metoprolol (such as LOPRESSOR™ and TOPROL-XL™), atenolol (such as TENORMIN™), pindolol (such as VISKEN™), and bisoprolol.

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more alpha blockers. Examples of suitable alpha blockers include prazosin, doxazosin (such as CARDURA™), phenoxybenzamine (such as DIBENZYLINE™), terazosin (such as HYTRIN™), CDRI-93/478 and CR-2991.

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more alpha-beta blockers; An example of a suitable alpha-beta blocker is labetalol (such as NOR ODYNE™ or TRANDATE™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more aldosterone receptor antagonists. Examples of suitable aldosterone receptor antagonists include eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more renin Inhibitors. Examples of suitable renin Inhibitors include alisklren (SPP tOO), SPP-500/600 and YS-004-39. in another embodiment, one or more compounds Formulae (I) through (I-32) may be coadministered with one or more central antiadrenergics. Examples of suitable central antiadrenergics Includes methyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ or CATAP ES-TTS™), guanfacine (such as TENEX™), and guanabenz (such as WYTENSIN™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more glycosides / inotropic agents. An example of a suitable glycoside / inotropic agent is digoxin (such as LANOXIN™).

In another embodiment, one or more compounds of Formulae (I) through (t-32) may be coadministered with one or more human B-type natriuretic peptides (hBNP) such as neslritide (such as NATRECOR™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more organic nitrates or an NO donors. "Nitric oxide donor" refers to a compound that donates, releases and/or directly or indirectly transfers a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothellum-derlved relaxing factor SO (ED F) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo. It also includes compounds that are substrates for nitric oxide synthase, Examples of suitable nitric oxide donors Include S-nltrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SP 5185, SPM 5186 and analogues thereof, sodium nitroprusside, nitroglycerin, Isosorblde dlnltrate, isosorblde mononitrate, molsidomine, SIN- and substrates of the various Isozymes of nitric oxide synthase, In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more soluble guanylate cyclase activator ("sGCa"). An example of a suitable soluble guanylate cyclase activator is BAY-41-8543.

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more bradyklnin agonists, In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more neutral endopeptldase Inhibitors. Examples of suitable neutral endopeptidase Inhibitors Include omapatrilat, fasidotril, mixanpril, sampatrilat, Z13752A , In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more endothellan antagonists. Examples of suitable endothelin antagonists Include ambrisentan, darusentan, J-104132, SPP-301 , TBC-37 1 , YM-62899, Υ -9174Θ and BMS- 193884.

In another embodiment, one or more compounds of Formulae (I) through {I-32) may be coadministered with one or more 3-hydroxy-3-methylglutaryl coenzyme A reductase Inhibitors.

Examples of suitable 3-hydroxy-3-methylglutaryl coenzyme A reductase Inhibitors include fluvastatin (such as LESCOL™), atorvastatln {such as LIPITOR™), lovastatin (such as AL.TOCOR™ or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatln (such as CRESTOR™), and simvastatin (such as ZOCOR™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with niacin or one or more nicotinic acid derivatives. Examples of suitable niacin or nicotinic acid derivatives include NIACOR™, NIASPAN™, NICOLAR™, and SLO-NIACIN™.

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more fibrlc acid derivatives. Examples of suitable fibric acid derivatives include clofibrate (such as ATROMID-S™), gemfibrozil (such as LOPID™), and fenofibrate (such as TRICOR™).

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more bile acid sequestants. Examples of suitable' ile acid sequestants include colestipol (such as COLESTID™), cholestyramine {such as LOCHOLEST™, PREVALITE™, QUESTRAN™, and QUESTRAN LIGHT™), colesevelam (such as WELCHOL™).

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more cholesterol absorbtion inhibitors. An example of a suitable cholesterol absorption inhibitor is ezetimlbe. (such as 2ETIA™).

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more cholesteryl ester transport protein Inhibitors. An example of a suitable cholesteryl ester transport protein inhibitor Is torcetraplb. n another embodiment, one or more compounds of Formulae (!) through (1-32) may be coadministered with one or more apical sodium-dependent bile acid cotransporter Inhibitors. Examples of suitable apical sodium-dependent bile acid cotransporter inhibitors Include SD-5613, AZD7806 and 264W94.

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more alpha glucosidase Inhibitors. Examples of suitable alpha glucosidase inhibitors include mlglitol (such as GLYSET™) and acarbose (such as PRECOSE™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more biguanides. Examples of suitable biguanides include rosiglltazone (such as AVANDAMET™) and metformin (such as GLUCOPHAGE™ and GLUCOPHAGE XR™).

In another embodiment, one or more compounds of Formulae (I) through (i-32) may be coadministered with one or more insulins. Examples of suitable Insulins include HUMALOG™, HUMALOG 50/50™, HUMALOG 75/25™, HUMULIN 50/50™, HUMALIN 75/25™, HUMALIN L™, HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN II LENTE™, ILETIN II NPH™, ILETIN II REGULAR™, LANTUS™, NOVOLIN 70/30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, VELOSULIN BR™, and EXUBERA™.

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more meglitnides. Examples of suitable meglitnides include repaglinide (such as PRANDIN™) and nategl!n!de (such as STARLIX™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more sulfonylureas, Examples of suitable sulfonylureas Include gllmeplrlde (such as AMARYL™), glyburlde (such as DIABETA™, GLYNASE PRESTAB™ or MICRONASE™), and glipizide (such as GLUCOTROL™ and GLUCOTROL XL™).

In another embodiment, one or more compounds of Formulae (I) through (I-32) may be coadministered with one or more thiazolldinediones, Examples of suitable thiazolldinedlones Include ploglltazone (such as ACT.OS™) and rosiglitazone (such as AVANDIA™).

In another embodiment, one or more compounds of Formulae (I) through (1-32) may be coadministered with one or more alpha-2-della ligands. Examples of suitable alpha-2-delta ligands include gabapentin, pregabalin (such as LYRICA™), |(1R,5R,6S)-6-(amlnomethyl)bicyclo[3.2.0]hept- 6-yl]acetic acid, 3-(1-aminomethyl-cyclohexy|methyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1-(1 H-tetrazol-5- ylmethylJ-cycloheptyJJ-methylamlne, (3S,4S)-(1-aminomethyt-3,4-dlmethyl-cyclopentyl)-acetic acid, (l o.SOiSoJ-iS-amlno-meth l-bicycloIS^.OJhept-S-y -acetic acid, (3S,5R)-3-aminomethyl-5-methyl- octanoic acid, (3S,5R)*3-amino-5-methyl-heptanolc acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-amlno-5-methyI-octanoic acid), (2S,4S)-4-(3-Ch!orophenoxy)praline, and (2S,4S)-4- (3-Fluorobenzyl)praline.

. Kits The present invention further comprises kits that are suitable for use In performing the methods of treatment or prevention described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present Invention and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.

In another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (1-32) and an angiotensin converting enzyme Inhibitor.

In another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (1-32) and an angiotensin II receptor antagonist.

In another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (1-32) and an aldosterone receptor antagonist. ' In another embodiment, the kit of the present invention comprises one or more compounds of Formulae (I) through (1-32) and a NO donor.

N. Compound Preparations Schemes The starting materials used herein are commercialfy available or may prepared by routine methods known to those of ordinary skill in the art (such as those methods disclosed In standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)).

The compounds of the present invention may be prepared using the methods Illustrated In the general synthetic schemes and experimental procedures detailed below. The general synthetic schemes are presented for purposes of illustration and are not intended to be limiting.

Scheme 1 III VI Scheme 1 outlines a general procedure for the preparation of 7-aryl pyrido[3,4-b]pyrazin of formula I, The starling material was the commercially available 6-chloropyridln-3-amlne II. 6-chloropyrldin- 3-amine II was protected, for example by converting to tert-butyl 6-chloropyridin-3-ylcBrbamate III by treatment with reagents such as di-tert-butyl dlcarbonate, (2E)-{[(tert-butoxycarbonyl)oxy]imino}{phenyl)acelonltri!e and tert-butyl phenyl carbonate. This reaction was carried out In solvents such as dloxane, tetrahydrofuran, water, ethyl acetate or dlchloromethane, in the presence or absence of inorganic bases such as potassium carbonate or sodium bicarbonate or organic bases such as triethylamine, 4-methylmorpholine, pyridine or fyW-dllsopropylethylamine at temperatures ranging from room temperature to 110 0 C. tert-butyl 6-chloropyrfdin-3-ylcarbamate III was converted to tert-butyl 6-chloro-4-fluoropyridln-3-ylcarbamate IV by metallation followed by quenching with an electrophilic fluorine source.

Lithation was achieved be treating tert-butyl 6-chloropyridIn-3-ylcarbamate 111 with an organolithium such as n-butyl lithium or t-butyl lithium in the presence or absence of additives such as Ν,Ν,Ν', N-tetramethylethylenediamine in solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from -80 0 C to 0 0 C. Suitable electrophlllc fluorine sources Include N- flurobenzenesulfonlmide.

Addition of primary and benzyllc amines to tert-butyl 6-chloro-4-fluoropyridln-3-ylcarbamale IV afforded amines of the formula V. This conversion was achieved by treatment of IV with amines in solvents such as ethyl alcohol, isopropyl alcohol, dimethylformamide, dimethylactemide, toluene, dioxane and dichloroethane in the presence or absence of Inorganic bases such as potassium carbonate or sodium bicarbonate or organic bases such as triethylamine, 4-methylmorphollne, pyridine or A/,W-diisopropylethylamlne at temperatures ranging from room temperature to 1 10 0 C. Amines of the formula V were converted to diamines of the formula VI by removing the carbamate protecting group under standard conditions, as described in Green, T., Wuts, P. Protecting Groups in Organic Synthesis, John Wiley & Sons, INC, Second edition, 1991 , pp 309-405.

The diamines of formula VI were converted to the diones of formula VII using various reaction procedures. In one procedure, this conversion was achieved by refluxing an aqueous solution of VI in the presence of oxalic acid and a catalytic amount of a mineral acid such as HCI. Alternatively, this conversion to structures of formula VI) was achieved by addition of either methyl chlorooxoacetate or oxalyl chloride to a solution of VI in the presence of an organic base such as triethylamine, 4-methylmorpholine, or V,/v-diisopropylethylamlne, at 0°C, followed by warming to either room temp or the reflux temperature of the solvent. Suitable solvents Include toluene, dichloromethane, dicholroethane, dioxane, or tetrahydrofuran.

The chloroimidate of formula VIII was prepared by a number of methods. In one procedure, a dlone of formula VII was heated to reflux In the presence of phosphorous oxychloride and a phase transfer catalyst such as tetraethylammonium chloride. Suitable solvents for this reaction include proplonitrlle or acetonitrile. In an alternate procedure, the formation of chloroimidate VII was achieved by dissolving VII in a suitable solvent such as dichloromethane, tetrahydrofuran, or dioxane and treating it with oxalyl chloride in the presence of a catalytic amount of dimethylformamide between 0 °C and room temperature.

The 6-am!nopyrazlnones of formula IX were prepared by the addition of various primary and secondary amines to chloroimidate VIII in the presence of an organic base such as triethylamine, 4-methylmorphollne, or Λ/,/V-diisopropylethylamine at temperatures ranging from 0 °C to room temperature. Suitable solvents Include dichloromethane, tetrahydrofuran, and dioxane, Formation of the desired pteridinone of formula I was prepared through a standard palladium catalyzed Suzuki coupling between chloride IX and suitable boronic acids, as described in iyaura, N„ Suzuki, A; Chem Rev. 1995, 95, 2457-2483. A solution of the chloride, IX, In a suitable solvent such as tetrahydrofuran or dioxane was heated to reflux In the presence of the desired boronic, an inorganic base such as sodium carbonate or cesium carbonate, and a palladium(O) source such pallad!um(ll) acetate or tetrakis(trlphenylphosphine)pat!adlurn to give compounds of formula I.

Scheme 2 Scheme 2 outlines an alternate conversion of tert-butyl 6-chloropyridin-3-ylcarbamate III to amines of formu\a V. lert-butyl 6-chloropyrldin-3-ylcarbamate III was converted to tert-butyl 6-chloro-4-lodopyridin-3- ylcarbamate X by metallation followed by quenching with an electrophilic iodine source, Llthatlon was achieved be treating tert-butyl 6-chloropyrldln-3-ylcarbamate IIJ with an organolithium such as n- butyl lithium or t-butyl lithium in the presence or absence of additives such as Ν,Ν,Ν',Ν'- tetramethylethylenediamine in solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from -80 0 C to 0 0 C. Suitable electrophilic iodine sources include molecular iodine and 1- iodopyrrolidine-2,5-dione. Addition of primary and benzylic amines to tert-butyl 6-chloro-4- iodopyrldln-3-ylcarbamate IV afforded amines of the formula V.

Amines of the formula X were converted to diamines of the formula V by standard coupling techniques as described in Ley, S.r Thomas, A.; Angew. Chem. Int. Ed. 2003, 42, 5400-5449. A solution of iodide, X, in a suitable solvent such as tetrahydrofuran, dioxane, toluene, benzene, N,N dlmethylformamlde, isopropanol, ethanol or proplonltrile was stirred at temperatures ranging from room temperature to reflux In the presence of the desired amine, a base such as sodium carbonate, cesium carbonate, potassium phosphate, or sodium terf-butoxlde and a palladium with llgand and/or a copper source. Suitable sources of palladium include pa!ladlum(ll) acetate, tetrakis(triphenylphosphine)palladium, dichlorot1 ,1 '-bis{diphenylphosphlno)ferrocenejpalladium (II) dichloromethane adduct and tris(dlbenzy!!deneacetone)dipalladium(0). Suitable ligands include lripheny!phosphine, tri-2-furylphosphine, 4,5-bis(diphenylphosphlne)-9-9-dimethylxathene, tricyclohexylphospine, ferf-butylphospine and 2,2'-bis(diphenylphosphino)-1 ,1 '-binapthyl. Suitable sources of copper Include copper(ll) acetate, copper{l) iodide and copper{l) chloride.

Scheme 3 Scheme 3 outlines a one-pot procedure for the conversion of diamlnopyrldlne of formula VI to amino substituted pyrazinone of formula IX.

The pyridine VI was dissolved in a solvent such as dichloromethane, tetrahydrofuran, or dloxane and cooled to 0 °C. The mixture was treated with oxaiyi chloride and allowed to slowly warm to room temperature. The reaction was typically mixed for 4-24 hours. The reaction mixture was then recooled to 0 °C, treated with an organic base such as trlethylamine, 4-methylmorphollne, or N,N- diisopropylethylamlne, followed by addition of the requisite primary or secondary amine leading to isolation of the desired amine of formula IX, Scheme 4 III V VII Scheme 4 outlines an alternate conversion of tert-butyl 6-chloropyrldin-3-ylcarbamate III to diones of formula VII. tert-butyl 6-chloropyridin-3-ylcarbamate III was converted to amines of formula V by meta!lation followed by quenching with an electrophlllc fluorine source and displacement of the fluorine with primary or benzyilc amines.

Liihation was achieved be treating tert-butyl 6-chloropyrldin-3-ylcarbamale III with an organolith!um such as n-butyl lithium or t-butyl lithium in the presence or absence of additives such as N,W,N',N'-tetramethylethylenediamfne In solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from -80 0 C to 0 0 C. Suitable electrophilic fluorine sources include N-flurobenzenesulfonimide, Addition of primary and benzylic amines to the Intermediate tert-butyl 6-chloro-4-fluoropyridin-3-ylcarbamate afforded amines of the formula V. This conversion was achieved by treatment of the crude tert-butyl 6-chloro-4-fluoropyridin-3-ylcerbamate with amines in solvents such as ethyl alcohol, Isopropyl alcohol, dimelhylformamide, dimethylactemide, toluene, dioxane and dichloroethane in the presence or absence of inorganic bases such as potassium carbonate or sodium bicarbonate or organic bases such as trlethylamine, 4-methylmorpholine, pyridine or Ν,Ν-diisopropylethylamine at temperatures ranging from room temperature to 110 0 C, Amines of the formula V were converted to diones of the formula VII by treatment with oxalic acid and additional protic acids such as HCI at temperatures ranging from 25 0 C to 110 0 C, or in a stepwise fashion as detailed in Scheme 1.

Compound Examples The following illustrate the synthesis of various compounds of the Formulae (l)-(|-32). Other compounds of this invention may be prepared using the methods Illustrated in these Examples, either alone or in combination with techniques generally known in the art.

Example 1 7-f6-methDXVPyridin-3'Vl¾-3-(plpera2in-1 -ylV1-f2-propoxyethyl)pyridor3.4-b1Pyra2ln-2M H)-one Step 1 : Preparation of tert-butyl 6-chloropyridin-3-ylcarbamate.

A solution of 5-amino-2-chloropyridine (30.94 g, 236 mmo!, Aldrich) and d)-tert-butyldlcarbonate (65.36 g, 299 mmol, Aldrich) in 1 ,4-dloxane (300 mL) was stirred at reflux for 20 hours. Additional dl- tert-butyldicarbonate (8.30 g, 38 mmol) was added and the reaction was stirred at reflux for 7 hours. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give a brown oil. The oil was triturated with diethyl ether and filtered to give tert-butyl 6-chloropyrldin-3-ylcarbamate as a tan solid. (49.84 g, 92% yield). Ή NMR (CDCI,) 6 8.24 (m, H), 7.96 (1 H), 7.27 (1H), 6.65 (1 H), 1.51 (9H).

Step 2: Preparation of tert-butyl 6-chloro-4-fluoropyrfdin-3-ylcarbamate, To a -63°C solution of tert-butyl 6-chloropyrldln-3-ylcarbamate (24.99 g, 109.3 mmol) and TMEDA (39 mL, 260.0 mmol; Aldrlch) In diethyl ether (700 mL) was added a 1.6M n-butyl lithium solution in hexane (193 mL, 308.8 mmoJ, Aldirch) over a period of 30 minutes while maintaining the temperature of the reaction at -60° to -50°C. The reaction was stirred at -60°C for an additional 10 minutes after the addition was complete then warmed to -10°C and stirred at -25° to - 0°C for 2,0 hours. The reaction was cooled to -60°C and a solution of W-fluorobenzenesulfonlmide (53.49 g, 169.6 mmol, Aldrlch) in tetrahydrofuran (155 mL) was added while keeping the temperature below - 50"C. It precipitated on addition and stirring became difficult. The reaction was then allowed to slowly warm to 0"C over 1 hour. The reaction was quenched with saturated ammonium chloride solution (400 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give an oily brown solid. The material was passed through a column of silica gel with 20% ethyl acetate/ hexane. The 6-chloro-4-fluoropyridin-3- ylcarbamate was obtained as a yellow solid. (15.88 g, 59% yield). 1H NMR <CDCI3) δ 9.09 (1H), 7.12 (1H), 6.55 (1H), 1.54 (S, 9H).

Step 3: Preparation of tert-butyl 6-chloro-4-r(2-proDoxyethyl)amlno1Pyridin-3-ylcarbarnate, A solution of tert-butyl 6-chloro-4-fluoropyridln-3-ylcarbamate (11.96 g, 48.5 mmol) and 2-n-propoxyethylamine (11.8 mL, 97.2 mmol, TCI) in ethanol (120 mL) was stirred at reflux for 22 hours. The reaction was cooled to room temperature and solvent was removed at reduced pressure to give a yellow solid which was triturated with diethyl ether and filtered to give 6-chloro-4-[(2-propoxyethyl)amino]pyridin-3-ylcarbamate as a white solid. (13.08 g, 82% yield). 1H NMR (CDCI3) J 7.92 (1H), 6.54 (1H), 5.77 (1H), 5.11 (1H), 3,65 (2H), 3.44 (2H), 3.34-3.29 <2H), 1.65-1.56 (2H), 1.49 (9H), 0.94 (3H), Step 4; Preparation of 6-chloro-N4-f2-propoxyethyl)pyridlne-3.4-diarnlne, A solution of tert-butyl 6-chloro-4-[(2-propoxyethyl)amino]pyrldln-3-ylcarbamate (7.08 g, 21.4 mmoi) in 1 ,4-dioxane (20 mL) was treated with 4N HCI in ,4-dioxane (100 mL) and stirred at room temperature for one hour, The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate solution, The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give 6-chloro-N4-(2-propoxyethyl)pyridlne-3,4-diamine as a brown oil. (4.93 g, 100% yield). 1H NMR (CDCIS) δ 7.63 (1 H), 6.45 (1 H), 4.67 (1H), 3.67 (2H), 3.43 (2H), 3.32-3.27 (2H), 2.92 (2H), 1.64-1.55 (2H), 0.93 (3H).

Step 5: Preparation of 3,7-dichloro-1-f2-propoxyethv0pyrldof3.4-blPyrazln-2M H -one.

A 0°C solution of 6-chloro-N4-(2-propoxyethyl)pyridine-3,4-diamine (2.80 g, 12.2 mmol) and diisopropylethylamlne (4.6 mL, 25.7 mmol) in dichloromethane (100 mL) was treated with methyl chlorooxoacetate(1.1 mL, 11.7 mmol, Aidrich), allowed to warm to room temperature and stirred for four hours. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and solvent was removed at reduced pressure. The residue was dissolved In toluene (30 mL) and heated at 105°C for four hours, The solvent was removed at reduced pressure and the resulting solid taken up In dichloromethane (100 mL) and treated with oxaiyi chloride (2.1 mL, 24.1 mmol) and DMF (3 drops). The reaction was stirred at room temperature for 6 hours. The solvent was removed at reduced pressure to give a brown solid. This was passed through a column of silica gel with 70% ethyl acetate/ hexane to give 3,7-dichloro-1 -(2-propoxyethy!)pyrido[3,4-b]pyrazin-2(1 H)-one as a white solid. (2.44 g, 66% yield). 1H NMR (CDCI3) δ 8.78 (1H), 7.59 (1 H), 4.40 (2H), 3.80 (2H), 3.35 (2H), 1.52-1.46 <2Η),·0,82 (3H).

Step 6: 7-chloro-3-fDiperazin-1-yl)-1-(2-propoxye¾hvnoyrldof3.4-blpyra2in-2(1 H)-on9.

A solution of 3,7-dichloro-1-(2-propoxyethyl)pyrido[3,4-bjpyrazin-2(1 H)-one (193 mg, 0.64 mmol), piperazine (118 mg, 0.91 mmo, Aidrich) and triethylamlne (0.15 mL, 1 ,07 mmol) in THF (3 mL) was slirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give a brown oil. This was passed through a column of silica gel with 80-100% ethyl acetate/ hexane to give 7-chloro-3-(pipera∑ln-1-yl)-1-(2- propoxyethyl)pyrido[3,4-b]pyrazln-2(1 H)-one. (183 mg, 72% yield).

Step 7: Preparation of 7-f6-methoxyDyridln-3-vn-3-fpipera2ln-1-yl)-1-f2-propoxye¾hvnpyridof3.4- b!pyrazin-2ClHVone.

A solution of 7-chloro-3-(plperazin-l-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazln-2(1H)-one (72 mg, 0.18 mmol) In ,4-dioxane (2.5 mL) was treated with tetrakis(trlphenylphosphlne) palladiurn(O) (19 mg, 0.016 mmol, Strem) and stirred at room temperature for five minutes. A warm solution of 2- methoxy-5-pyridineboronic acid (41 mg, 0.27 mmol, Frontier) In ethanol (0.5 mL) and 2.0 aqueous sodium carbonate 1.5 mL) were added. The mixture was refluxed for 2.0 hours, filtered hot through celite and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and passed through a column of silica gel with 2% methanol/ dichloromethane. Fractions were concentrated at reduced pressure and triturated with diethyl ether. The 7-(6'methoxypyridln-3-yl)-3-(piperazin-1-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin- 2(1H)-one was obtained as a pink powder. 1H N R (CDCIs) .58.77 - 8,74 (2H), 8.27 - 8.23 (1H), 7.64 (1H), 6.85 (1H), 4.42 (2H), 4.00 - 3.95 (7H), 3.79 (2H), 3,37 (2H), 3.07 - 3.03 (4H), 1.53 - 1.46 (2H), 0.78 (3H); HRMS m/z 425.2293 (calcd for M+H, 425.2296).

Example 2 . 3-fns.4SV2.5-dlazabicvclor2.2,nhept-2>yll-7-f6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3.4- btoyrazin-2nH¾-one Prepared as described in example 1 using (1 ,4R)-2,5-diazabicyclo[2.2.1]heptane in step 6. 1H NMR (CDCIa) .68.74 - 8.70 (2H), 8.41 - 8.22 (1H), 7,59 (1 H), 6.84 ( H)P 4.39 (2H), 4.00 (3H), 3.85 - 3.73 (5H), 3.37 (2H), 3.17 (2H), 1.87 - 1.76 (2H), 1.54 - 1.47 (3H), 0.87 - 0.76 (4H); HRMS /z 437.2316 (calcd for M+H, 437.2296).

Example 3 7- 6-methoxypyridln-3-ylV3-morDholin^ Prepared as described in example 1 using morpho!ine in step 6. 1H NMR (CDCI3) δ 8.77-8.75 (2H), 8.24 (1 H), 7.64 (1 H), 6.86 (1 H), 4.42 (2H), 4.02-4.00 (7H), 3,86- 3.83 (4H), 3.79 (2H), 3.36 (2H), 1.53-1.46 (2H), 0.78 (3H); HRMS m/z 426.2109 (calcd for M+H, 426.2136).

Example 4 3-^3-hvdroxypiperldln-1-vn-7-f6-methoxypyridln-3-vn-1-f2-propoxyethyl Pyrldor3.4-blPyrazin-2fl H - one.

Prepared as described In example 1 using 3-hydroxyplperidlne In step 6. Ή NMR (CDCIi) δ 8.76 (2H), 8.28-6,25 (1H), 7.65 (1H), 6.86 (1H), 4,43 (2H), 4, 17-4.14 (2H), 4.06 (1H), 4.01 (3H), 3.84-3.69 (4H), 3.37 (2H), 2.84 (1H), 1.97-1.92 (1H), 1.88-1.84 (2H), 1.54-1.47 (2H), 0.78 (3H); HRMS /z 440.2280 (calcd for M+H, 440.2292).

Example 5 3-^.(2-hvdroxyethyl)plpera2ln-1-yl 7-f6-methoxypyridln-3-ylV1-(2-DroDoxyethyl yrM 2(1HV-one Step 1: Preparation of tert-butyl 6-chloropyrtdin-3-ylc3rbarnate.

A solution of 5-amino-2-chloropyridlne (30.94 g, 236 mmol, Aldrich) and di-tert-butyldicarbonate (65.36 g, 299 mmol, Aldrich) In 1,4-dioxane (300 mL) was stirred at reflux for 20 hours. Additional dl- terf-butyldicarbonate (8,30 g, 38 mmol) was added and the reaction was stirred at reflux for 7 hours. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give a brown oil. The oil was triturated with diethyl ether and Altered to give tert-butyl 6-chloropyrldln*3- ylcarbamate as a tan solid. (49,84 g, 92% yield). 1H NM (CDCI3) δ 8.24 (m, 1 H), 7,96 (1H), 7.27 <1H), 6.65 (1H), 1.51 (9H).

Step 2: Preparation of tert-butyl 6-chloro-4-fluoropyridln-3-ylcarbamate.

To a -63°C solution of tert-butyl 6-chloropyridin-3-ylcarbamate (24.99 g, 109.3 mmol) and T EDA (39 mL, 260.0 mmol, Aldrich) in diethyl ether (700 mL) was added a 1.6 n-butyl lithium solution in hexane (193 mL, 308.8 mmol, Atdlrch) over a period of 30 minutes while maintaining the temperature of the reaction at -60° to -50Ό.. ΤΙΊΘ reaction was stirred at -60DC for an additional 10 minutes after the addition was complete then warmed to -10°C and stirred at -25° to -10°C for 2.0 hours. The reaction was cooled to -60°C and a solution of N-fiuorobenzenesulfonimlde (53.49 g, 169.6 mmol, Aldrich) in tetrahydrofuran (155 mL) was added while keeping the temperature below -50°C. It precipitated on addition and stirring became difficult. The reaction was then allowed to slowly warm to 0°C over 1 hour, The reaction was quenched with saturated ammonium chloride solution (400 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 250 mL), The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give an oily brown solid. The material was passed through a cofumn of silica gel with 20% ethyl acetate/ hexane. The 6-chloro-4-fluoropyrldin-3- ylcarbamate was obtained as a yellow solid. (15.88 g, 59% yield). 1H N R (CDCI3) 6 9.09 (1 H), 7.12 (1 H), 6.55 (1H), 1.54 (s, 9H).

Step 3: Preparation of tert-butyl 6-chl0ro-4-r(2-propoxyethyl)aminoipyridtn-3-ylcarbamate.

A solution of tert-butyl 6-chloro-4-ftuoropyridln-3-ylcarbamate (11.96 g, 48.5 mmol) and 2-n- propoxyethyfamine {11.8 mL, 97.2 mmol, TCI) in ethanol (120 mL) was stirred at reflux for 22 hours.

The reaction was cooled to room temperature and solvent was removed at reduced pressure to give a yellow solid which was triturated with diethyl ether and filtered to give 6-chloro-4-[(2- propoxyethyl)amlno]pyrldln-3-ylcarbamate as a white solid. (13.08 g, 82% yield). 1H NMR (CDCI3) δ 7.92 (1H), 6.54 (1H), 5.77 (1H), 5.11 (1H), 3.65 (2H), 3,44 (2H), 3.34-3.29 (2H), 1.65-1 ,56 (2H), 1.49 (9H), 0.94 (3H).

■Step 4: Preparation of 6-chloro-N4-f2-propoxyethyltoyridlne-3.4-diamlne, A solution of tert-butyl 6-chloro-4-[(2-propoxyethyl)amlno]pyridin-3-ylcarbamate (7.08 g, 21.4 mmol) in 1 ,4-dioxane (20 mL) was treated with 4N HCI In 1 ,4-dioxane (100 mL) and stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed al reduced pressure to give 6-chloro-N*-(2-propoxyethyl)pyrldine-3,4-diamine as a brown oil. (4.93 g, 100% yield). 1H NMR (CDCI3) δ 7.63 (1 H), 6.45 (1 H), 4.67 (1 H), 3.67 (2H), 3.43 (2H), 3.32-3.27 <2H)t 2.92 (2H), 1.64-1.55 (2H), 0.93 (3H).

Step 5: Preparation of 3,7-dichloro-1-f2-propoxyethyl yridof3.4-blPyra2ln-2f1HVone.

A 0°C solution of 6-chloro-N -(2-propoxyethy|)pyridine-3,4-diamine (2.80 g, 12.2 mmol) and diisopropylethylamine (4.6 mL, 25.7 mmol) In dichloromelhane (100 mL) was treated with methyl chlorooxoacelate(1.1 mL, 11.7 mmol, Aldrich), allowed to warm to room temperature and stirred for four hours. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and solvent was removed at reduced pressure. The residue was dissolved In toluene (30 mL) and heated at 105°C for four hours. The solvent was removed at reduced pressure and the resulting solid taken up in dichloromethane (100 mL) and treated with oxalyf chloride (2. mL, 24.1 mmol) and DMF (3 drops). The reaction was stirred at room temperature for 6 hours. The solvent was removed at reduced pressure to give a brown solid. This . was passed through a column of silica gel with 70% ethyl acetate/ hexane to give 3,7-dichloro-1-(2- propoxyethyt)pyrldo[3,4-b]pyrazln-2(1 H)-one as a while solid. (2.44 g, 66% yield). 1H N R (CDCI3) δ 8.78 (1 H), 7.59 (1H), 4.40 (2H), 3.80 (2H), 3.35 (2H), 1.52-1.46 (2H), 0.82 (3H).

In the alternative, the conversion of 6-chloro-N4-(2-propoxyethyl)pyrldtne-3,4-diamine from Step 3 to the 7-chloro-1-(2-propoxyethy/)pyrido[4,3-b]pyTazine-2,3(1Hl4H)-dlone of Step 5 can be conducted in a one-pot synthesis using an aqueous solvent as described in Steps V to VII in Scheme 4.

Step 6; 7-chloro-3-r4-(2-hvdroxyethvnDlperazin-1-vn-1-(2-propoxyethyltoyrldor3.4-blPyra2ln-2(1 H)-one, A solution of 3(7-d!chloro-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2{1 H)-one (200 mg, 0.68 mmol), 1-(2-hydroxyethyl)pIperazine (117 mg, 0.90 mmo, Aldrich) and triethylamlne (0.27 mL, 1.94 mmol) In THF (3 mL) was "stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give 7-chloro-3-[4-(2- hydroxyethyl)plperazin-1-yl] 1-(2^ropoxyethyl)pyrido[3,4-b]pyra2in-2(1 H)-one. (218 mg, 83% yield). 1 H NMR (CDCIs) δ 8.48 (1H), 7.34 (1 H ), 4.33-4.30 (2H), 4.04-4.00 (4H), 3.76-3.72 <2H), 3.69-3.65 (2H), 3.38-3.34 (2H), 2.67-2.64 (4H), 2.62-2.58 (2H), 1.55-1.48 (2H), 0.87-0.82 <3H), Step 7: Preparation of 3-f4-(2-hvdroxethyl loerazin-1-vn-7-f6-metrioxypyridiri-3-vn-1 -f2- propoxyethvnpyridof3,4-blpyrazln-2(1 H)-one.

A solution of 7-chloro-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1-C2-propoxyethyl)pyrido[3,4-b]pyrazin- 2(1 H)-one (218 mg, 0.55 mmol) In ,4-dioxane (3.0 mL) was treated with tetrakis(triphenylphosphlne) palladium(O) (19 mg, 0.016 mmol, Strem) and stirred at room temperature for five minutes, A warm solution of 2-methoxy-5-pyrldlneboronlc acid (41 mg, 0.27 mmol, Frontier) in ethanof (0.5 mL) and 2.0 M aqueous sodium carbonate 1.5 mL) were added. The mixture was refluxed for 2.0 hours, filtered hot through celite and the filtrate, was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the layers were separated. The aqueous layer was extracted with ethyl acetate, The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and passed through a column of silica gel with 2.5% methanol/ dichloromethane. Fractions were concentrated at reduced pressure and triturated with diethyl ether. The 7-(6-methoxypyridln-3-yl)-3-(plperazin-1 -yl)-1 -{2- propoxyethyl)pyrido[3,4-b]pyrazin-2(1 H)-one was obtained as a pink powder. 1H NMR (CDCI3) δ 8.77-8.76 (2H), 8,24 (1 H), 7.64 (1 H), 6.86 (1 H), 4.43 (2H), 4.06-4.03 (4H), 4.00 (3H), 3.79 (2H), 3.71-3.67 (2H), 3.37 (2H), 2.78 (1H), 2.72-2.69 (4H), 2.66-2.62 (2H), 1.53-1.46 (2H), 0.78 (3H); HRMS m/z 469.2572 (calcd for M+H, 469,2558).

Example 6 3-f3-mvdroxymethvnpiperidin-1-yll-7-f6-methoxypyridin-3-yl)-1 -f2-propoxyethyl)pyridof3.4-blDyrazin- 2(1 HVone.

Prepared as described in example 1 using plperldin-3-ylmethanol in step 6. 1H NMR (CDCIs) δ 8.69 (1 H), 3.67 (1H,), 8.16 (1 H), 7.56 (1 H), 6.78 (1 H), 4.39-4.32 (2H), 3.94-3.81 (6H), 3.79-3.64 (4H), 3.56-3.52 (1H), 3.32 (2H), 2.05-1.95 (1H), 1.84-1.78 (1 H), 1.70-1.62 (2H), 1.50- 1 ,41 (3H), 0.73 (3H); HRMS m/z 454.2419 (calcd for M+H, 454.2449).

Example 7 tert-butyl M-r7-f6-methoxypyrldin-3-ylV2-oxo-1 -f2-Dropoxyethv -1.2-dlhvdropyrldo[3,4-blpyra2ln-3- yllplperazin-l-vnacetate Prepared as in example 1 using tert-butyl 2-{piperazln-1 -yl)acetate In step 6. 1H NMR (CDCI3) δ 8.77-8.75 (2H), 8.24 (1H), 7.64 (1 H), 6.86 (1H), 4.42 <2H), 4.08 (4H), 4.01 (3H), 3.78 (2H), 3.37 (2H), 3.19 (2H), 2.77 (4H), 1.53-1.44 (11 H), 0.78 (3H). HRMS m/z 539.2949 (calcd for M+H, 539.2976).

Example 8 f4-[7-f6-methoxyPyridin-3-yl)-2-oxo-1-f2-propoxyetriyl)-1.2-dihvdropyridof3.4-blpyrazin-3-yl1piperazin- -yltecetic acid.

A solution of tert-butyl {4-[7-(6-methoxypyridirt-3-yl)-2-oxo-1-(2-propoxyethyl)-1,2-dlliydropyridot314-b]pyrazln-3-yl]plperazin1-yl)acetate (174 mg, 0.32 mmol) in dich!oromethane (3 mL) was treated with trifluoroacetlc acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether, concentrated and recrystallized from ethyl acetate and hexane and filtered. The {4-[7-(6-methoxypyrldin-3-yl)-2-oxo-1-(2-propoxyethyl)-1 ,2-dihydropyrido[3,4-b]pyrazin-3-yl]plperazin1-yl}acetic acid was obtained as a white solid. (81 mg, 52% yield). , Ή NMR (CD3OD) δ 8.76-8.74 (2H), 8.24 (1H), 8.09 (1 H), 7.02 (1 H), 4.61 (2H), 4.40 (4H), 4.17 (2H), 4.02 (3H), 3.84 (2H), 3.61-3.59 (4H), 3.38 (2H), 1.47-1.40 (2H), 0.73 (3H). HRMS m/z 483.2361 (calcd for M+H, 483.2350).

Example 9 3-f(3S)-4-f2-hvdroxe(hyl)-3-methylplperazln-1-vn-7-f6-methoxypyrldin-3-vn-1-(2- Dropoxvethvltovrldof3.4-blPyrazln-2f1 H¾-one.

Prepared as in example 1 using 2-((S)-2-methylpiperazin-1-y!)ethanol in step 6. 1H NMR (CDCIa) δ Θ.77-8.75 (2H), 8.24 (1H), 7.64 (1 H), 6.86 (1H), 4.44-4.40 (4H), 4.00 (3H), 3.79 (2H), 3.74-3.67 (1 H), 3.63-3.57 (2H), 3.41-3.35 (3H), 3.04-2.96 (2H), 2.76-2.72 (2H), 2.53-2.43 (1H), 2.41-2.36 ( 1H), 1.53-1.44 (2H), 1.17 (3H), 0.78 (3H). HRMS m/z 483.2732 (calcd for M+H, 483.2714).

Example 10 3-f4-(3-hvdroxpropyl)-3.5-dimeth ylpiperazin- 1 -vH-7-f 6-methoxypyridin-3-yl )-1 -( 2- p ropoxyeth yl) pyddof 3.4 -btoyrazln-2( 1 H Vone .

Prepared as in exampi© 1 using 3-{2,6-dimethylplperazln-1-yl)propan-1-ol in step 6. Ή NMR (CDCI3) S 8.76-8.75 (2H), 8.24 (1 H), 7.63 (1H), 8.86 (1H), 4.78-4.73 (2H), 4.42 (2H), 4.00 (3H), 3.97 (1 H), 3,81-3.77 (4H), 3.37 (2H), 2.93-2.86 (4H), 2.70 (2H), 1.77-1.73 (2H), 1.53-1.46 (2H), 1.23 (6H), 0,78 (3H). HRMS m/z 5 1.3026 (calcd for M+H, 511.3027).

Example 11 3-r4-f3-hvdroxpropyl)plDerazln-1-yl 7-f6-melho?<vpyridin-3-vn-1-f2-DropoxyethvnDyrldor3.4-b1Pyrazin- 2(1 H)-one. .

Prepared as in example 1 using 3-{piperazin-1-yl)propan-1-ol in step 6.

H NMR (CDCI3) 8 8.78-8.76 (2H), 8.25 (1 H), 7.65 (1 H), 6.86 (1H), 4.42 (2H), 4.13-4.06 (4H), 4.01 (3H), 3.86 (2H), 3.79 (2H), 3.37 (2H), 2.76 (6H), 1.83 (2H). 1.53-1.46 (2H), 0.78 (3H). HR S m/z 483.2747 (oalcd for M+H, 483.2714).

Example 12 3-f4-f2-hvdroxet yl>-1.4-diazepan-1-yll-7-f6-melhoxypyridin-3-yl -1 -f2-propoxyethyl>pyrldof3.4-b)pyrBZin-2(1 HVona, Prepared as in example 1 using 2-(1 ,4-diazepan-1 -yl)ethanol in step 6. 1H NMR (COCI3) δ 8.75-8.73 (2H), 8.24 (1H), 7,60 (1 H), 6.86 (1 H), 4.41 (2H), 4.13-4.11 (2H), 4.05-4.00 (5H), 3.78 (2H), 3.64 (2H), 3.38 (2H), 3.03 (2H). 2.82-2.76 (4H), 2.12 (2H), 1.54-1.47 (2H), 0.80 (3H). HRMS m/z 483.2720 (calcd for M+H, 483.2714).

Example 13 7-(4-chlorophenv0-3-(4-f2-hydroxyethyltoipera^^ 0Π9 Prepared as in example 1 using 2-(piperazin-1-yl)ethanol is step 6 and 4-chlorophenylboronlc acid in step 7. HRMS m/z 472.2177 (calcd for M+H, 472.2115) Example 14 3-f4-f2-hvdroxyethvnpiperazin-1-yl)-7-(4-hvdroxyphenyl)-1-f2-propoxyethvnpyridor3,4-b'lPyra2in- 2M H)-on9 Prepared as in example 1 using 2-(pfperazin-1-yi)ethanol in step 6 and 4- ydroxyphenyiboronlc acid in step 7. HRMS /z 454.2456 (calcd for M+H, 454.2454).

Example 15 7-(4>fdimet yl3rnino)'2-methylp enyl)-3-f4-(2-hvdroxyethv0plperaztn-1-yl -1-(2- propoxyethyl)pyrldof3,4-blpyrazin-2(1 H)-one Prepared as in example 1 using 2-(piperazln-1-yl)ethanol in' step 6 and 4-(dimetbylamino)-2-methylphenylboronic acid in step 7. HRMS m/z 496.2983 (calcd for M+H, 496.3036), Example 16 7-f3-chlorophenyl)-3- -f2-hvdroxyethyl)plperazin-1-yl)-1-f2-propoxyethyl)pyridof3.4-blDyr one Prepared as in example 1 using 2-{piperazln-1 -yl)ethanol In step 6 and 3-chlorophenylboronic acid in step 7. HRMS m/z 472.2095(calcd for M+H, 472.2115).

Example 17 3-f4-f2-hvdroxyethvnpiperazln-1-yn-7-f4-methoxyrjhenyl^1-f2-propoxyethyl pyrldof3.4-blPyrazin- 2( H¾-one Prepared as In example 1 using 2-(piperazin-1 -yl)ethanol In step 6 and 4-methoxyphenylboronic acid in step 7. HRMS m/z 468.2527 (calcd for M+H, 468.2611 ).

Example 8 7-f2.4-difluorophenvn-3-f4-f2-hvdroxyethyl)piperazin-1 -vn-1 -(2-propoxy.ethvnpyridof3.4-blPyrazin- 2M H -one Prepared as in example 1 using 2-{piperazln-1-yl)ethanol in step 6 and 2,4-difluorophenylboronic acid in step 7. H S m/z 474.2299 (calcd for M+H, 474.2317).

Example 19 7-(4-fathylsulfonvi henyl)-3-M-f2-rivdroxyelhvnplDerazln-1-vn-1-(2-propoxyBthyl yridor3.4- blpyrazin-2(1 W-one Prepared as in example 1 using 2-(piperazin-1-y!)et anol In step 6 and 4- (ethylsulfonyl)phenylboronlc acid in step 7. HRMS m/z 530.2369 (ca!cd for M+H, 530.2437).

Example 20 7-^2-fluoro-3-metrioxyphenyl)-3-f4-(2- ivdroxyethyl)DiPerazin-1-yl¾-1-f2-propoxyethvnpyrldof3.4- blpvrazin-2M H)-one Prepared as in example 1 using 2-(piperazJn-1-yl)ethanol in step 6 and 2-fluoro-3-methoxyphenylboronlc acid in step 7. HRMS m/z 4 B6.2464 (calcd for M+H, 486.2516).

Example 21 3.(4.(2-hvdroxyethyl)piperazin-1-vO-7-M-tsopro 2f1 H)-one Prepared as In example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 4-isopropoxyphenylboronlc acid in step 7. HR S m/z 496.2932 (calcd for M+H, 496.2924).

Example 22 3./4-f2-rtvdroxyel yl)piperazin-1-yl)-7-fispQuinolin-5-vi)-1-(2-propoxyethvnpyrldoF3.4-blDyra2in-2(1 H)- one Prepared as in example 1 using 2-{piperazin-1-yl)et anol in step 6 and isoquinolin-5-yl-5-boronic acid In step 7. HRMS m/z 489.2621 (calcd for M+H, 489.2621 ).

Example 23 S-M-^- vdrDXvethyl piperazin- -vn^-^-fhvdroxymethyliphenyli- -fZ-propoxyethyllpyrfdofS^- blpyrazin-2(1 H)-one Prepared as In example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 4- (bydroxymelhyl)phenyJboronic acid in step 7. .HRMS m/z 468,2537 {calcd for M+H, 468.2611 ). 7-M-ethoxyDhenvn-3-f4-f2-hvdroxyethv()Diperazin-1-yl)-1-(2-proDoxyethvnDyrldof3.4-blDVrazin- 2(1 H)-one - Prepared as in example 1 using 2-(piperazin-1 -yl)ethano) in step 6 and 4-ethoxyphen lboronic acid in step 7. HRMS m/z 482.2747 (calcd for M+H, 482,2767).

Example 25 7-f4-fluoro-3-methylDhenvn-3-f4-(2-hvdrQxyethvnDlperazln-1-yl)-1-f2-propoxyethyl)Dyridof3,4' blpyrazin-2(1 Hi-one Prepared as In example 1 using 2-(piperazln-1-yl)ethanol In step 6 and 4-fluoro-3-methylphenylboronic acid in step 7. HRMS m/z 470.2620 (calcd for M+H, 470,2567), Example 26 7-f2,3-difluorophenvn-3-(4-(2- vdroxyethyl)pipera2ln-1-ylV1-(2-propoxyethvnpyridof3,4-b1pyrazln- 2(1 H)-one prepared as in example 1 using 2-(piperaztn-i-yl)ethanpl in step 6 and 2,3-d!fluorophenylboronic acid in step 7. HR S m z 474.2396 (calcd for M+H, 474.2317).

Example 27 3-i4-f2-hvdroxyethyl)pipera2ln-1-yl)-1-f2-propoxyethylV7-o-tolylPyridof3.4-b1pyrazin-2(1 H)-one Prepared as in example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 4-methylphenylboronic acid in step 7. HRMS m/z 452.2651 {calcd for M+H, 452.2661). 7-f5-acetylthioDhen-2-yl)-3-(4-(2- ydroxyethyl iperazin-1>vi -1-f2-propoxyethyl)pyridof3,4-b pyrazin- 2Π Hi-one Prepared as in exampie 1 using 2-(piperazin-1-yl)ethanol In step 6 and 5-acetylthiophen-2-yl-2-boronlc acid in step 7. HRMS m/z 486.2128 (calcd for M+H, 486.2175).

Example 29 3-f4'(2-hvdroxyet yl)piperazin-1-yl)-7-(3-me ^ 2(1 Hk>ne Prepared as In example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 3-methoxyphenylboronic acid in step 7. HR S m/z 468.2603 (calcd for +H, 468.261 1 ).

Example 30 3-(4-(2-hvdroxyethvnp)perazin-1-ylV7-(3-fhvdroxymethvnp envn-1-(2-propoxyethyl)pyrido[3.4- blpyraz!n-2f1 H)-one Prepared as in example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 3- (hydroxymethyl)phenylboronic acid in step 7. HRMS m/z 468.2550 (calcd for M+H, 468.2611 ).

Example 31 3-(4-f2-hvdroxyethvnpiperazln-1-yl 1-f2-propoxye<hyl 7-fpyrldin-3-vnpyridof3.4-blpyrazin-2(1H)-one Prepared as In example 1 using 2-(piperaz!n-1-yl)ethanol in step 6 and pyridin-3-yl-3-boronlc acid In step 7. HRMS m/z 439.2361 (calcd fcr M+H, 439.2458).

Example 32 7-(3-ethoxyphenyl)-3-(4 2-hvdroxyetM^ 2f1H)-one Prepared as in example 1 using 2-(piperazin-1-yl)et anol in step 6 and 3-8t oxyphenylboronic acid in step 7. HRMS m/z 482.2743 (calcd for M+H, 482.2767). 7-f3-fluoro-4-methoxyp enyli-3-(4-(2-hvdroxyethylblperazin-1-yl)-1 -f2-proDoxyethyl yrldof3,4- blPyrazln-2f1 H -one Prepared as in example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 3-fluoro-4-met oxyphenylboronic acid in step 7. HRMS m/z 486.2608 (calcd for M+H, 486.2516).

Example 34 7-(5-c loro-2-fluorophenyl)-3-(4-(2-hydroxyethyl)pip8razin-1-yl -1 -f2-prQPoxyethyl)pyridof3.4- blPyrazln-2(1 HVone Prepared as in example 1 using 2-(piperazin-1-yl)ethanol in step 6 and 5-chloro-2- fluorophenylboronic acid In step 7. HR S m/z 490.1991 (calcd for +Hv 490.2021).

Example 35 3-f4-(2-hvdroxyethvnDlDerazln-1-yl)-7-f4-methoxy-3-methylphenylV1-(2-propQxyethyl yridoi3,4- blpyra2ln-2MH -one Prepared as in example 1 using 2-(piperazin-1-yl)et anol in step 6 and 4-methoxy-3- methylp enylboronic acid In step 7. HRMS m/z 482.2771 (calcd for M+H, 482.2767).

Example 36 3 4-f2-hvdrDxyelhyl¾piperazin-1-yl 1-f2-propoxyethvn-7-m-tolylpyrido[3.4-blpyrazin-2f1H)-one Prepared as in example 1 using 2-(piperazln-1-yl)ethanol In step 6 and 3-met ylphenylboronic acid in step 7. HRMS m/z 452.2672 (calcd for M+H, 452.2661).

Example 37 3-f4-(2-hvdroxyel yl)piperazin-1-yl)-7-(2-rivdroxyDhenv))-1-(2-propoxyethyl)pyridol3.4-Mpyrazln- Prepared as in example 1 using 2-(piperazin-1-yl)ethanol in slep 6 and 2-hydroxyphenylboronic acid in step 7. HRMS m/z 454.2383 (calcd for +H, 454.2383). 7-f2-fluorophenyl)-3-f4-f2-hvdroxyet yl)Dlperazin-1 -yl)-1-f2-prQPoxyethvi)pyridof3,4-blPyrazin-2 Hl- one Prepared as in example 1 using 2-(plperazin-1-yl)ethanol In step 6 and 2-fluorophenylboronic acid in step 7. HRMS m/z 456.2417 (calcd for M+H, 456,241 1 ).

Example 39 3-f4-et ylpjperazln--1-yll-7-(6-rnethoxypyridin-3-yl -1-(2-propoxyethvnpyrldof3.4-blpyraz(n-2(1H)-one Prepared as in example 1 using 1-ethylpiperazlne In step 6. LRMS m/z 453.3 (calcd for M+H, 453.5).

Example 40 1- .2-dihvdro-7-f6-methoxyDyrldln-3-yl)-2-oxo-1-f2-bropoxye(hvnpyrido[3,4-■lblPyrazlri-3- yl iPerldlne-3-carboxamide Prepared as in example 1 using plper!dine-3-carboxamide in step 6. 1H NMR (CDCI3) δ 8,82 - 8,78 (2H), 8.28 - 8.26 ( H), 7.69 (1H), 7,26 (1H), 6.88- 6.85 (1H), 5.67 (1H), 4.52 - 4.40 <2H), 4.23 - 4,18 (1H), 4.02 (3H), 3.90 - 3.71 (4H), 3.44 - 3.37 (2H), 2.71 - 2.66 (1 H), 2.31 - 2.25 (1 H), 1.92 - 1.77 (3H), 1.60-.45 (3H), 0.90 - 0.80 (3H); LRMS m/z 467,2 (calcd for M+H, 467.5), Example 41 1-(1.2-dihvdro-7-f6-melhoxyDyridin-3-yl)-2-oxo-1-(2-propoxyethyl)Pyrldof3.4-blPyra2iri-3- vnpiperldlne-4-carboxamlde Prepared as In example 1 using plperidine-4-carboxamide In step 6. 1H NMR (CDCI3) 6 8.78 - 8,74 (2H), 8.26 - 8.25 (1 H), 7.66 {1 H), 6.88 - 6,85 (1 H), 5.58 - 5.53 (2H), 4.99 - 4,96 (2H), 4.46 - 4.28 (2H), 4.02 (3H), 3.84 - 3.79 (2H), 3.44 - 3.37 (2H), 3. 3 - 3.07 <2H), 2.65 (1 H), 2.06 - 1.86 (3H), 1.56 - 1.47 (3H), 0.90 - 0.82 (3H); LRMS m/z 467,2 {celcd for M+H, 467.5), Example 42 3-f3-hvdroxyPyrrolidin-1 -yl)-7-f6-m8lhoxyoyridln-3-yl -1 -f2-propoxyethvnpyrldor3.4-blDyra2in-2h H)- one Prepared as in example 1 using pyrrolidin-3-ol In step 6. Ή NMR (CDCI3) δ 8.74 - 8.71 (2H), 8.26 -8.23 (1 H), 7.61 (1 H), 6,86 - 6.84 <1 H), 4.73 (1 H), 4.43 - 4.01 <9H), 3.79 - 3,76 (2H), 3.40 - 3.37 (2H), 2.08 (3H), 1.57 - 1.39 (2H), 0.90 - 0.82 (3H); LRMS m/z 426.2 (calcd for M+H, 426.5).

Example 43 3.(4-f2-hvdrQxy-2-methylDroPvnplDeraziri-1-vn-7-f6-me¾hoxypyridin-3-yl)-1-(2- propoxyelhvDp yrJdof3,4-blpyrazin-2C 1 H)-one Prepared as in example 1 using 2-methyl-1-(plperazin-1-yl)propan-2-ol in step 6. 1H NMR (CDCI3) δ 8.75 (2H), 8.24 - 8.22 (1 H), 7.61 (1H), 6.84 - 6.82 (1 H>, 4.42 - 4.39 (2H), 3.99 (7H), 3.81 - 3.76 (2H), 3.38 (2H), 3.10 - 3.00 < 1 H), 2.81 - 2.78 (4H), 2.39 (2H), 1.53 - 1.46 (2H), 1.25 (6H)( 0.81 -0.75 (3H); LRMS m/z 497.4 (calcd for M+H, 497.6).

Example 44 3.f4~ff2S,3RV3-hvdroxybulan-2-yl)p|perazin-1-vh-7-{6-methoxyDyridin>3-vn-1 >f2- propoxyethvi)pyrldof3,4-blPyrazln-2{ 1 H¾-one Prepared as in example 1 using (2R,3S)-3-(piperazin-1 -yl)butan-2-ol in step 6. HRMS m/z 497.4 (calcd for M+H, 497.6).

Example 45 SI 3-f4-(f2R.3R¾-3- vdroxybulan-2-yl ipera2in-1-yl)-7-f6-rnelhoxyPyrldin-3-vn-1-f2- Dropoxyethyl)pyrldof3,4-bipyrazin-2f 1 H)-one Prepared as In example 1 using (2R,3R)-3-(piperazin-1-yl)butan-2-ol in step 6. HRMS m/z 497.4 (calcd for M+H, 497.6).

Example 46 3-(4>ffSV2-hvdroxypropyl)piperazin-1-yl)-7-(6-methoxyPyrldln-3-vn-1-(2-propoxyethyl pyrldof3l4- blpyrazln-2f1H)-one Prepared as in example 1 using (S)-1 -(piperazin-1 -yl)propan-2-ol in step 6. 1H NMR (CDCI.) 5 8,76 (2H), 8.25 (1 H), 7.62 (1H), 6.85 - 6.82 (1 H), 4.71 (2H), 4,43 - 3.91 (7H), 3.80 - 3.74 (2H), 3.38 - 3.35 (2H), 2.83 - 2.80 (2H), 2.57 - 2.54 (2H), 2.38 - 2.29 (2H), 1.54 - 1.45 (2H), 1.32 - 1.25 (5H), 0.96 - 0.79 (3H); HRMS m/z 483.3 (calcd for M+H, 483.6).

Example 47 3-(4-ffR1-2-hvdroxypropynpiDerazln-1-vn-7-(6-methoxyDyridln-3-yl -1-f2-propoxyetr)vnpyridor3.4» blpyrazln-2M H)-one Prepared as In example 1 using (R)-1-(plperazin-1-yl)propan-2-oHn step 6. HRMS m/z 483,3 (calcd for M+H, 483,6).

Example 48 3-M-(3-hvdroxypropylM,4-dlazepan-1-yl)-7-(6-methoxyp^^^ b)pyrazin-2f1 H)-one Prepared as in example 1 using 3-(1,4-diazepan-1-yl)propan-1-ol in step 6. HRMS m/z 497.4 (caicd for M+H, 497.6), O. in Vitro Assays Method 1 : Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay The ICB0 of a test compound can be measured using an in vitro assay using PDE5 enzyme isolated from human platelets. The IC50 Is the concentration of test compound required to Inhibit the hydrolysis of cGMP to G P by the PDE5 enzyme by 50% relative to the activity of uninhibited controls. The PDE5 enzyme for use in the assay can be obtained from human platelets by appropriate modification of the method of Thompson, WJ ef ai Biochemistry 18(23), 5228-5237, 1979, as described by Ballard SA et a!.; J. Urology 159(6), 2164-2171 , 1998. The PDE5 enzyme so obtained can be used to catalyze the hydrolysis of [3H]cGMP (Amersham Biosciences) to 5' nucleotide [3H]GMP. The [3H]GMP binds to yttrium silicate SPA beads (Amersham Biosciences) and Is detected by scintillation counting. More specifically, the effect of a test compound at different concentrations can be evaluated in the assay by contacting the compound with a fixed amount of PDE5 enzyme in the presence of substrate (cGMP or cAMP in a 3;1 ratio uniabelled to (3HJ-labeled). Scintillation counting can be used as described above to determine relative PDE5 enzyme activity. The Inhibition of PDE5 enzyme activity Is then calculated relative to total PDE5 enzyme activity of uninhibited controls.

PDE5 ICso Assay: 96-well microtiter plate format .

Reagents Buffer A: ί 20 mM Trts-HCI, 5 mM MgC!z, pH 7.4 Buffer B: ∑ 2 mg/ml BSA In Buffer A (enzyme buffer) cGMP substrate i; Final concentration of 500 nM In assay The amount of 3H-labeled substrate added depends upon the specific activity of [3H]cGMP, and (he cGMP substrate is diluted with a 10 mM stock of cold cGMP in Buffer A for a final substrate concentration of 500 nM iri the assay, PDE enzyme; Prepared In Buffer B. The dilution factor is determined by enzyme activity.

SPA beads: 20 mg/m! suspension prepared in dH20.

Positive Control Negative Control Standard/Test compound 2 μΙ 100% D SO 2 μΙ 100% DMSO 2 μΙ Standard/Test compound μΙ Buffer A 25 μΙ Buffer A 25 μΐ Buffer A μΙ Enzyme 25 μΙ Buffer B 25 μΙ Enzyme 50 μΙ Substrate 50 μΙ Substrate 50 μΙ Substrate 50 μΙ SPA to stop 50 μΙ SPA to stop 50 μΙ SPA to stop Stocks of standard and test compounds are prepared at 5 mM In 100% DM SO. The compound is serially diluted in a dilution plate using a 10-polnt ½ log dilution format. 2 μ| of the compound dilution Is added in duplicate to the wells of the assay plate. 2 μ| of 00% DMSO are added to designated control wells. 25 μΙ of Buffer A are added to all wells. 25 μΙ of Buffer B are added to the negative control wells. 25 μΙ of enzyme are added to the remaining wells. 50 μΙ of substrate are added to each well. Plates are sealed and incubated for 60 minutes on a plate shaker at 30 C. 50 μΙ of SPA beads are added to stop the reaction. The plates are again sealed and shaken for 15 minutes to allow the beads to bind the GMP product. The beads are allowed to settle for 30 minutes and then read on a NXT TopCount scintillation counter. Data are analyzed with a curve fitting application for piate-based screening. Percent inhibition in this assay is calculated as follows: Inhibition (%) = [(mean maximum - compound value/ (mean maximum - mean minimum)] x 100.

The IC6D value Is determined from sigmoid dose-response curves of enzyme activity versus compound concentration.

Method 2: Alternative Human Platelet PDE5 Enzyme Inhibition Scintillation Proximity Assay The lC6o of a test compound also can be measured in an alternative in vitro assay that varies from Method 1 as described below: PDE5 !¾ Assay: 96-well mlcrotiter plate format Reagents Buffer A: 20 mM Trls-HCI, 5 mM MgCI2, pH 7.4 Buffer B: 2 mg/ml BSA in Buffer A (enzyme buffer) cGMP substrate: Final concentration of 50 nM in assay The amount of 3H-labe!ed substrate added depends upon the specific activity of [ H]cG P, and It is diluted In Buffer A.

PDE enzyme: Prepared In Buffer B. The dilution factor Is determined by enzyme activity, SPA beads: 4 mg/ml suspension prepared in dHzO.

Positive Control Neoative Control Standard/Test compound 3 μ1 100% DMSO 3 μΐ 100% DMSO 3 μΙ Standard/Test compound 27 μΙ Buffer A 27 μΙ Buffer A 27 μΙ Buffer A μΙ Enzyme 30 μΙ Buffer B 30 μΙ Enzyme μΙ Substrate 30 pi Substrate 30 μΙ Substrate μΙ SPA to stop 30 pi SPA to stop 30 μ I SPA to stop Stocks of standard and test compound are prepared at 2 rnM in 100% DMSO. The test compound is serially diluted in a dilution plate using an 8-point 1 /5 log dilution format such that the starting concentration in the assay Is 2 μΜ for an Initial \CS0 screen, 27 μΙ of Buffer A are added to the wells of the assay plates. From the dilution plate, 3 μΙ of diluted compound is delivered in duplicate or 3 μΙ of 100 % DMSO (for positive and negative controls) are added. 30 μΙ of enzyme are added. For the negative control wells, Buffer B Is substituted tn place of the enzyme. 30 μΙ of labeled substrate are added to all wells.

After incubating for 60 minutes at room temperature, the reaction is stopped with the addition of 30 μΙ of the yttrium silicate beads. These beads are dense and require constant agitation while being added to the plate. The plates are sealed and shaken on a plate shaker for fifteen minutes to allow the beads to bind the GMP product.

After allowing the beads to settle for 30 minutes, plates are read on a NXT TopCount scintillation counter and the data are analyzed as follows. Percent Inhibition values are calculated using the means of the 0% and 100% controls on each plate. The estimates of the 4-parameters of the logistic, sigmoid dose-response model are then calculated using the well-level percent inhibition value for the compound. The formula for the four-parameter logistic model may be expressed as Y = ( (a - d) / (1 + ( X / c)b) ) + d, where Y Is the response, X is the concentration, a ts the lower asymptote (minimum response), d Is the upper asymptote (maximum response), c is the model IC5o (In the same units as X), and b is the slope (as described in De Lean, A., P. J. Munson, and D. Rodbard ("Simultaneous analysis of families of sigmoldal curves: application to bloassay, radioligand assay, and physiological dose-response curves." Am. J. Physiol. 235(2): E97-E102, 1978). These estimates are used to calculate the concentration that corresponds to 50% inhibition, Compounds were tested in accordance with Method 2 above yielding the IC50 values described in Table C, Table C PDE5 IC50 PDE5 IC50 Example # Example # (nMJ (nM) 1 3.26 25 1.87 2 ■2,38 26 47.1 3 1.01 27 ' 9.31 4 0.225 28 43.1 0.203 29 3.07 6 0.313 30 311 7 O.0B3 31 45.8 8 0.517 32 15B 9 0.24Θ 33 13.6 0.193 34 12.6 1 1 0.177 35 1.69 12 0.721 36 423 PDE5 IC50 PDE5 1C50 Example # Example # (n ) (nM) 13 1.35 37 18.1 14 ' 832 38 42.2 1190 39 0.217 16 3.34 40 0.296 17 7.71 41 0.249 18 29.9 42 0.421 19 102 43 0.208 1.59 44 0.33 21 413 45 0.295 22 >2000 46 0.306 23 1 90 47 0.226 24 1400 48 1.07 P. Ex Vivo Assays Method 3: Aortic Rino Assay A test compound can be tested in an ex vivo assay that measures the direct relaxation of rat aortic rings exposed to the compound, In this assay, a test compound elicits a relaxation of an aortic ring by enhancing the cG P signal evoked by a stable exogenous nitric oxide donor, dlethyltrlamine NONOate (dlazen-1-ium-1 , 2-diolate) ("DETA-NO"). An EC50, with 95% confidence intervals, for compound-evoked relaxation Is calculated as an Index of potency. The ECso is the concentration of a test compound which produces 50% of the maximum possible effective response for a test compound.

Male Sprague-Dawley rats (250-350g) are asphyxiated using C02 gas and their thoracic aortas carefully excised and placed in Krebs buffer. The aortas are then carefully dissected free of connective tissue and divided into 8 sections, each 3-4mm in length.

Aortic rings are suspended between parallel stainless steel wires in a water jacketed (37°C), 15 mL tissue bath under a resting tension of 1 gram. Tension is measured using isometric tension transducers and recorded using Ponemah tissue platform system! Each preparation is allowed to equilibrate for at least 60 minutes prior to compound testing, During this time, the tissues are also incubBted with 200 uM NG-monomethyl L-argln!ne ("L-NMMA"), and the incubation media changed every 15 to 20 minutes (L-NMMA is added after each wash to maintain the final concentration at 200u in each tissue bath), Following the equilibration period, baseline tensions are recorded for each tissue. The vasoconstrictor response lo phenylepherine (1 uM) is assessed and when the response to phenylepherine reaches a maximum, vascular reactivity is subsequently assessed by a challenge of acetylcholine {1 uM). Following another washout period, a second baseline value is recorded after adding the vasoconstrictor noradrenaline (25-n ) to each bath and Incubating the tissues for a time period (about 15 minutes) sufficient for the tissues to achieve a stable tone. An exogenous nitric oxide drive is supplied using the stable nitric oxide donor, DETA-NO. The concentration of DETA-NO is titrated (cumulatively In half-log increments) to achieve approximately 5 to 15% relaxation of the noradrenaline-evoked preconstriction. Cumulative concentration-response curves are constructed In a single ring, typically using 5 doses/ ring and allowing 15 minutes between each addition.

Method 4: Alternative Aortic Ring Assay Method 3 can be modified to provide an alternative protocol for to measuring the direct relaxation of rat aortic rings exposed to a test compound. This alternative method varies from Method 3 as described below: For the alternative method, the endothelium is first removed by gently rubbing the lumen of the vessel together between the fingers prior to preparing the rings (denuded rings). The resting tension is set at 2 grams and the vasoconstrictor response to a maximal concentration of phenylepherine (1 μΜ) is assessed, followed {after a washout period) by two further exposures to 300 nM of pheylephrine. The concentration-response relationship to noradrenaline Is constructed in each tissue over concentration range 0, 1 to 300 nM. After another washout period, the tissues are constricted with an EC9D concentration of noradrenaline for compound testing.

Q. Biological Protocols--/n Vivo Assays Method 5: Culex™ Assay The effect of a test compound on systemic arterial blood pressure can be evaluated in a conscious pre-cannulated spontaneously hypertensive rat ("SHR") model. This assay is conducted using an automated blood sampler ("ABS") system. The Culex™ ABS system (Bioanalytical System, Inc., West Lafayette, IN) comprises a laptop computer, four control units and metabolic cages. This ABS system allows for the collection of multiple blood samples from a single rat without causing undue stress to the animal. In addition, the ABS system allows for the collection of urine samples that can be potentially used for biomarker identifications. Through this approach, efficacy and standard pharmacokinetic studies are conducted In the conscious ' unrestrained SHR rats simultaneously to define the relationship between plasma free drug concentration or potential biomarker(s) and pharmacological effect (reduction of mean arterial blood pressure).

SHR rats at 12 to 16 weeks of age, weighing about 300g, undergo surgerlcal cannulatlon of both jugular veins and the right carotid artery. After surgical recovery, animals are placed In the Culex™ cages and tethered to a movement-responsive arm with a sensor that controls cage movement when the animal moves to prevent the catheters from being twisted. Connections are made between the right jugular catheter and the Culex™ sterile tubing set for blood sampling, and the left jugular catheter for compound administration, and the catheter In the rlghl carotid artery Is connected to a pressure transducer for monitoring blood pressure. To keep the patency of the catheters, the right jugular cannula Is maintained by the "tend" function of the Culex™ that flushes the catheter with 20 μί. heparin saline (10 units/mL) every 12 minutes or between sampling events, and the left Jugular cannula Is filled with heparin saline (20 units/mL). The patency of the right carotid cannula Is maintained by slow infusion of heparin saline either directly into the extend tubing when blood pressure Is not recorded or through the pressure transducer during the blood pressure monitoring. Animals are allowed to acclimate for at least two hours before compound evaluation, A test compound may be administered intravenously or by oral gavage. Biood sampling protocols (sampling time and volume) are programmed using the Culex™ software. The total amount of blood withdrawn from each animal will not exceed 750 L 24 hrs and 0 mL/kg within two weeks. Heart rate, blood pressure, and drug concentration are monitored. Systemic arterial blood pressure and heart rate are recorded by PONE AH (Gould Instrument System, Valley View, OH), a pressure transducer through a data acquisition system for recording blood pressure and heart rate, for 6 to 24 hours based on experimental protocol. Mean arterial blood pressure (primary endpoint) is analyzed for assessing the efficacy of the compound.

Blood samples are analyzed for measuring plasma drug concentration, using the LC/MS/ S method described below, and for evaluating potential blomarkers, LC/MR/MS Method Sample Preparation: Plasma samples (50 μΐ unknown, control or blank) are mixed with 10 μΐ acetonitrile:water or a standard solution of a test compound and 150 μΐ of Internal standard solution (100 ng/mL of a test compound In acetonitrile). The mixture is centrifuged at 3000 rpm for 5 min, and 125 μΐ of the supernatant transferred to a 96 well plate. The solvent is evaporated under a stream of nitrogen and the residue Is reconstituted with 80 μΐ acetonltrlle/0.1% aqueous formic acid (20:80 v/v).

A 20 /L volume of each prepared sample is injected onto a Phenomenex Synergi 4 μνη MAX- RP 2.0 x 75 mm column and eluted at 0.4 mL/min using gradient elutlon from 0.1% aqueous formic acid {mobile phase A) to acetonitrile (mobile phase B), The gradient program consists of initial application of 90% mobile phase A, followed by a linear gradient to 75% mobile phase B from 0.2 to 1.15 mln after Injection and held at 75% mobile phase B until 2.0 min, The mobile phase was linearly changed back to 90% mobile phase A from 2.00 to 2.10 minutes, and the next injection took place at 3,00 min. Detection was performed by mass spectrometry using positive Ion electrospray (ESI) with multiple reaction monitoring of the transitions m/z 454.00 (MH+ a test compound) -* m/z 408.00„m/z 466.24 (MH+ a test compound) -· 409.33 . The ion spray voltagea is set at 5000. A calibration curve Is constructed by using peak area ratios of the analyte relative to the internal standard. Subject concentrations are determined by inverse prediction from their peak area ratios against the calibration curve.

Method 6: Implantation of Radio Transmitters and Subsequent Blood Pressure Screening by Telemetry Ιη Spontaneously Hypertensive Rats SHR Rats are anesthetized with isofiurane gas via an isoflurane anesthesia machine that is calibrated to deliver Isoflurane over a range of percentages as oxygen passes through the machine's inner chambers. The animals are placed in an induction chamber and administered isoflurane at 4-5% to reach a surgical plane of anesthesia. They are then maintained at 1-2% during the surgical procedure via a nose cone, with isoflurane delivered via a smaller isoflurane anesthesia device on the surgical table.

Following administration of anesthesia, the rats are implanted with transmitters using aseptic procedures with commercially available sterile radio-telemetry units (Data Sciences, International, Rosevllle, MN 551 13-1136). Prior to surgery the surgical field is shaved, scrubbed with Dial™ brand antimicrobial solution (containing 4% chlorhexldlne gluconate and 4% Isopropyl alcohol) followed by an application of Iodine (10%) spray solution. A 2.5 to 3.0 cm laparotomy Is preformed and the radio-telemetry units implanted into the abdomen, with the catheter tip Inserted into the abdominal aorta. Baby Weitlaner retractors are used to retain soft tissue. A 1 cm section of the abdominal aorta is partially dissected and that section cross-clamped briefly, punctured with a 21-gauge needle and the transmitter catheter tip introduced Into the vessel and secured by a single 4.0 silk suture anchored to the adjacent psoas muscle. The transmitter body Is then inserted into the abdominal cavity and simultaneously secured to the abdominal muscle wall while closing with running 4.0 silk suture. The skin layer is closed with subdermal continuous 4.0 absorbable suture. A subcutaneous (s.c.) administration of marcalne followed by a topical S9 194591/2 application of iodine Is administered into and around the suture line, respectively, upon closing. All rats receive a postoperative Injection of buprenorphlne @ O.OSmg/kg, s.c. before regaining consciousness. A typical dose volume for a 0,300kg rat will be 0.050ml. The rats must be fully recovered from their operative anesthesia before the administration of buprenorphlne. They then receive the same dose once dally for 2 consecutive days, unless the animal demonstrates that it is in compromising postoperative pain.

Following surgery, the rats are returned to their cages and housed individually on solid bottom caging with paper bedding. A period of no less than 7 days Is allowed for recovery before exp rimental rocedures are initiated. It has been observed that the rats are typically hypertensive for several days following surgery and return to "normotensive" levels by approximately the 7lh day post-surgery. They are fed standard rat chow and water ad libitum throughout the experimental time line.

Test compounds are administered intragastrically (i.g.) via gavage, using of a stainless steel, 2½ Inch, 19 gauge gavage needle with a balled end. For single daily dosing, the target volume is 3.33 ml/kg, l.g. The dose volume for a test compound is approximately 1 ml/ rat. The vehicles In which a lest compound is administered is methylcel!uiose (0.5%) + Tween 80 (0.1%) In 50mM citrate buffer pH=5.0.

Blood pressure data will be obtained using Data Sciences International's data acquisition program (Version 3.0). Blood pressure samples are recorded at 1.5-3 minute intervals for a 5 second duration 24 hours per day for the entire study. This data Is processed by Data Science's data analysis software into averages of a desired time (nervals. All other data reduction is performed In Microsoft Excel™ spreadsheets.

All documents mentioned In this application are expressly incorporated by reference as if fully set forth at length. When Introducing elements of the present invention or the preferred embodimenl(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are Intended to be inclusive and mean that there may be additional elements other than the listed elements, Material which is outside the scope of the claims does not constitute a part of the claimed invention.

Claims

WO We A or a pharmaceutically acceptable salt of the wherein the compound has the structure of Formula and Is selected from the group consisting of aryl and 3 to 10 membered ring heterocycyl wherein said R2 aryl and heterocyclyl substituents may be optionally substituted with one or more substituents independently selected the group consisting of wherein said and cycioalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and and are independently selected from the group consisting of hydrogen and wherein said alkyl may be optionally substituted with one or more substituents Independently selected from the group consisting of carboxy and together with the nitrogen to which they are attached form a partially or fully saturated 3 to 14 membered ring wherein the heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of and wherein said alkynyl and cycioalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and and and aryl heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and and are independently selected from the group consisting of and wherein said and alkyl may be optionally substituted with one or more substltuents independently selected from the group consisting of hydroxy and and said alkenyl and alkynyl substituents may be optionally substituted with one more substituents Independently selected from the group consisting of and Is wherein said R8 substituent may be optionally substituted with one or more substituents independently selected from the group consisting of and wherein said alkenyl and alkynyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and and and R802 are independently selected from the group consisting of alkenyl and wherein when alkyl is said methyl may be optionally substituted with or 3 fluoro when said alkyl comprises at least two carbon said alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of and and and alkenyl and alkynyl substltuents may be optionally substituted with one or more substltuents independently selected from the group consisting of and The compound of claim 1 R2 Is selected from the group consisting of and wherein the and pyrldinyl may be optionally substituted with one or more substltuents independently selected from the group consisting of and wherein said alkyl and alkenyl substituents may be optionally substituted with one or more substltuents independently selected from the group consisting of and and and are independently selected from the group consisting of hydrogen and wherein said alkyl may be optionally substituted with one or more substltuents Independently selected from the group consisting of hydroxy and and R together the nitrogen to which they attached form a partially or fully saturated 5 to 7 membered ring wherein the 5 to 7 membered ring heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of and said alkyi may be optionally substituted with or substltuent selected from the group consisting of and and are independently selected from the group consisting of hydrogen and wherein said and alkyi may be optionally s with one or more substituents independently selected from the group consisting of and is substituted with selected from the group consisting of hydrogen and alkyi wherein when said is said methyl may be optionally substituted with or 3 fluoro and when said alkyi comprises at least two carbon said alkyi may be optionally substituted with one or more substituents independently selected from the group consisting of and The compound of claim 2 wherein Is to substituted with wherein is to optionally substituted with or 3 fluoro or a pharmaceutically acceptable salt The compound of claim 3 R2 Is selected from the group consisting of and wherein the and pyridlnyl may be optionally substituted with one or more substituents independently selected from the group consisting of wherein said alkyi may be optionally substituted with one or more and and are independently selected from the group consisting of hydrogen and or a pharmaceutically acceptable salt The compound of claim 4 the and pyridlnyl may be optionally substituted with one or more substituents Independently selected from the group consisting of and or a pharmaceutically acceptable salt The compound of claim 3 Rw and together with the nitrogen to which are attached form a haterocyclyl selected from the group consisting of and wherein the and diazepinyl may be optionally substituted with one or substltuents Independently selected from the group consisting of and wherein said alkyl substltuent may be optionally substituted one more substltuent selected from the group consisting of and and and are Independently selected from the group consisting of hydrogen and or a pharmaceutically acceptable salt The compound of claim together with the nitrogen to which they are attached form a haterocyclyl selected from the group consisting of piperazlnyl and morphollnyl wherein the piperazlnyl and morphollnyl may be optionally substituted with one or more substltuents selected from the group consisting of and or a pharmaceutically acceptable salt The compound of claim 3 wherein and together with the nitrogen to which they are attached form a piperazlnyl wherein the piperazlnyl may be optionally substituted with one or more substltuents Independently selected from the group consisting of and or a pharmaceutically acceptable salt The compound of claim 3 R2 is selected from the group consisting of phenyl and wherein the phenyl and pyrldinyl may be optionally substituted with one or more substltuents selected from the group consisting of and and and together with the nitrogen to which they are attached a heterocyclyl selected from the group consisting of and morphollnyl wherein the and morphollnyl may be optionally substituted with one or more substituents selected from the group consisting of and or a pharmaceutically acceptable salt compound of claim 9 R2 Is pyrldlnyl substituted with and together with the nitrogen to which they are attached form a optionally substituted with one or more substituents selected from the group consisting of and and R8 is or a pharmaceutically acceptable salt A or a pharmaceutically acceptable salt of the wherein the compound has the structure of Formula and wherein optionally substituted with one or more substituents Independently selected from the group consisting of wherein and aikynyl and cycloalkyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and and are independently selected from the group consisting of hydrogen and alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of carboxy and and together with the nitrogen to which they are attached form a 5 to 7 membered partially or fully saturated wherein the heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of and wherein said alkynyl and cycloalkyi substituents may be optionally substituted with one or more substituents independently selected from the group consisting of heterocyclyl substituents may be optionally substituted with one or more substituents independently selected from the group consisting of and Rfl03 and are independently selected from the group consisting of and wherein said and alkyl may be optionally substituted with one or more substituents independently selected from the group consisting of and and said and alkenyl and alkynyl substituents may be optionally substituted with one or more substituents Independently selected from the group consisting of and and is selected from the group consisting of and ethyl and wherein said ethyl and propyl may be optionally substituted with 1 or 3 fluoro The compound of claim wherein R2 is wherein and are Independently selected from the group consisting of and or a pharmaceutically acceptable salt 194591 The compound of claim 12 wherein and are each selected from the group consisting of and or a pharmaceutically acceptable salt The compound of claim wherein and are each and is methpx or a pharmaceutically acceptable The compound of claim 11 together with the nitrogen to which they are attached form a heterocyclyl selected from the group consisting of and wherein the piper and diazeplnyl ma be optionally substituted with one or more substituents Independently selected from the group consisting of and or a acceptable salt A compound of claim 1 selected from the group consisting n 1 ydroxyet oxyp propoxyet 1 1 and pharmaceutically acceptable salts A compound according to claim 1 that Is or a pharmaceutically acceptable salts A pharmaceutical composition comprising a compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt a pharmaceutically acceptable Use of a amount of a compound of any one of claims 1 to or a pharmaceutically acceptable salt in the preparation of a medicament for treating a condition selected from the group consisting of cardiovascular metabolic central nervous system pulmonary sexual pain and renal The use of claim 18 wherein the cardiovascular condition Is 21 Use of a amount of a compound of any one of claims 1 to or a pharmaceutically acceptable salt in the preparation of a medicament for promoting neurorestoration in a LUZZATTO insufficientOCRQuality